System for non-invasive measurement using cameras and time of flight detection

ABSTRACT

A measurement system comprises a pulsed laser diode array that includes one or more Bragg reflectors, and wherein the light generated by the array penetrates tissue comprising skin. At least some of the wavelengths of light are in the near infrared. The detection system is synchronized to the laser diode array and comprises an infrared camera and a first receiver comprising a plurality of detectors. The first receiver comprises one or more detector arrays and performs a time-of-flight measurement. The measurement system generates an image, the detection system non-invasively measures blood in blood vessels within or below a dermis layer within the skin based at least in part on near-infrared diffuse reflection from the skin, and the detection system measures absorption of hemoglobin between 700 and 1300 nanometers wavelength range. A processor compares the absorption of hemoglobin between different tissue spatial locations, and the measurement system processes the time-of-flight measurement.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/597,383 filedOct. 9, 2019, which is a continuation of U.S. Ser. No. 16/241,628 filedJan. 7, 2019, now U.S. Pat. No. 10,441,176 issued Oct. 15, 2019, whichis a continuation of U.S. Ser. No. 16/015,737 filed Jun. 22, 2018, nowU.S. Pat. No. 10,172,523 issued Jan. 8, 2019, which is a continuation ofU.S. Ser. No. 15/594,053 filed May 12, 2017, now U.S. Pat. No.10,188,299 issued Jan. 29, 2019, which is a continuation of U.S.application Ser. No. 14/875,709 filed Oct. 6, 2015, now U.S. Pat. No.9,651,533 issued May 16, 2017, which is a continuation of U.S.application Ser. No. 14/108,986 filed Dec. 17, 2013, now U.S. Pat. No.9,164,032 issued Oct. 20, 2015, which claims the benefit of U.S.provisional application Ser. No. 61/747,487 filed Dec. 31, 2012, thedisclosures of which are hereby incorporated in their entirety byreference herein.

U.S. Ser. No. 16/597,383 is also a continuation of U.S. application Ser.No. 16/506,885 filed Jul. 9, 2019, which is a continuation of U.S.application Ser. No. 16/272,069 filed Feb. 11, 2019, which is acontinuation of U.S. application Ser. No. 16/029,611 filed Jul. 8, 2018(now U.S. Pat. No. 10,201,283), which is a continuation of U.S.application Ser. No. 15/888,052 filed Feb. 4, 2018 (now U.S. Pat. No.10,136,819), which is a continuation of U.S. application Ser. No.15/212,549 filed Jul. 18, 2016 (now U.S. Pat. No. 9,885,698), which is acontinuation of U.S. application Ser. No. 14/650,897 filed Jun. 10, 2015(now U.S. Pat. No. 9,494,567), which is a U.S. National Phase ofPCT/US2013/075700 filed Dec. 17, 2013, which claims the benefit of U.S.provisional application Ser. No. 61/747,472 filed Dec. 31, 2012, thedisclosures of all of which are hereby incorporated in their entirety byreference herein.

U.S. application Ser. No. 16/506,885 is also a continuation of U.S.application Ser. No. 16/004,359 filed Jun. 9, 2018, which is acontinuation of U.S. application Ser. No. 14/109,007 filed Dec. 17, 2013(now U.S. Pat. No. 9,993,159), which claims the benefit of U.S.provisional application Ser. No. 61/747,553 filed Dec. 31, 2012, thedisclosures of all of which are hereby incorporated in their entirety byreference herein.

U.S. application Ser. No. 16/506,885 is also a continuation of U.S.application Ser. No. 16/188,194 filed Nov. 12, 2018 (now U.S. Pat. No.10,386,230), which is a continuation of U.S. application Ser. No.16/004,154 filed Jun. 8, 2018 (now U.S. Pat. No. 10,126,283), which is acontinuation of U.S. application Ser. No. 15/855,201 filed Dec. 27, 2017(now U.S. Pat. No. 9,995,722), which is a continuation of U.S.application Ser. No. 15/711,907 filed Sep. 21, 2017 (now U.S. Pat. No.9,897,584), which is a divisional of U.S. application Ser. No.15/357,225 filed Nov. 21, 2016 (now U.S. Pat. No. 9,797,876), which is acontinuation of U.S. application Ser. No. 14/650,981 filed Jun. 10, 2015(now U.S. Pat. No. 9,500,634), which is the U.S. national phase of PCTApplication No. PCT/US2013/075767 filed Dec. 17, 2013, which claims thebenefit of U.S. provisional application Ser. No. 61/747,485 filed Dec.31, 2012, the disclosures of all of which are hereby incorporated byreference in their entirety.

U.S. application Ser. No. 16/506,885 is also a continuation of U.S.application Ser. No. 16/241,628 filed Jan. 7, 2019 (now U.S. Pat. No.10,441,176), which is a continuation of U.S. Ser. No. 16/015,737 filedJun. 22, 2018 (now U.S. Pat. No. 10,172,523), which is a continuation ofU.S. Ser. No. 15/594,053 filed May 12, 2017 (now U.S. Pat. No.10,188,299), which is a continuation of U.S. application Ser. No.14/875,709 filed Oct. 6, 2015 (now U.S. Pat. No. 9,651,533), which is acontinuation of U.S. application Ser. No. 14/108,986 filed Dec. 17, 2013(now U.S. Pat. No. 9,164,032), which claims the benefit of U.S.provisional application Ser. No. 61/747,487 filed Dec. 31, 2012, thedisclosures of all of which are hereby incorporated in their entirety byreference herein.

U.S. application Ser. No. 16/506,885 is also a continuation of U.S.application Ser. No. 16/284,514 filed Feb. 25, 2019, which is acontinuation of U.S. application Ser. No. 16/016,649 filed Jun. 24, 2018(now U.S. Pat. No. 10,213,113), which is a continuation of U.S.application Ser. No. 15/860,065 filed Jan. 2, 2018 (now U.S. Pat. No.10,098,546), which is a Continuation of U.S. application Ser. No.15/686,198 filed Aug. 25, 2017 (now U.S. Pat. No. 9,861,286), which is acontinuation of U.S. application Ser. No. 15/357,136 filed Nov. 21, 2016(now U.S. Pat. No. 9,757,040), which is a continuation of U.S.application Ser. No. 14/651,367 filed Jun. 11, 2015 (now U.S. Pat. No.9,500,635), which is the U.S. national phase of PCT Application No.PCT/US2013/075736 filed Dec. 17, 2013, which claims the benefit of U.S.provisional application Ser. No. 61/747,477 filed Dec. 31, 2012 and U.S.provisional application Ser. No. 61/754,698 filed Jan. 21, 2013, thedisclosures of all of which are hereby incorporated by reference intheir entirety.

This application is related to U.S. provisional application Ser. No.61/747,477 filed Dec. 31, 2012; Ser. No. 61/747,481 filed Dec. 31, 2012;Ser. No. 61/747,485 filed Dec. 31, 2012; Ser. No. 61/747,472 filed Dec.31, 2012; Ser. No. 61/747,492 filed Dec. 31, 2012; Ser. No. 61/747,553filed Dec. 31, 2012; and Ser. No. 61/754,698 filed Jan. 21, 2013, thedisclosures of which are hereby incorporated in their entirety byreference herein.

This application is also related to International Application No.PCT/US2013/075700 (Publication No. WO/2014/105520) entitledNear-Infrared Lasers For Non-Invasive Monitoring Of Glucose, Ketones,HBA1C, And Other Blood Constituents; International ApplicationPCT/US2013/075736 (Publication No. WO/2014/105521) entitled Short-WaveInfrared Super-Continuum Lasers For Early Detection Of Dental Caries;U.S. application Ser. No. 14/108,995 (Publication No. 2014/0188092)entitled Focused Near-Infrared Lasers For Non-Invasive Vasectomy AndOther Thermal Coagulation Or Occlusion Procedures; InternationalApplication PCT/US2013/075767 (Publication No. WO/2014/143276) entitledShort-Wave Infrared Super-Continuum Lasers For Natural Gas LeakDetection, Exploration, And Other Active Remote Sensing Applications;U.S. application Ser. No. 14/108,974 (Publication No. 2014/0188094)entitled Non-Invasive Treatment Of Varicose Veins; and U.S. applicationSer. No. 14/109,007 (Publication No. 2014/0236021A1, now U.S. Pat. No.9,993,159) entitled Near-Infrared Super-Continuum Lasers For EarlyDetection Of Breast And Other Cancers, the disclosures of all of whichare hereby incorporated in their entirety by reference herein.

BACKGROUND

With the growing obesity epidemic, the number of individuals withdiabetes is also increasing dramatically. For example, there are over200 million people who have diabetes. Diabetes control requiresmonitoring of the glucose level, and most glucose measuring systemsavailable commercially require drawing of blood. Depending on theseverity of the diabetes, a patient may have to draw blood and measureglucose four to six times a day. This may be extremely painful andinconvenient for many people. In addition, for some groups, such assoldiers in the battlefield, it may be dangerous to have to measureperiodically their glucose level with finger pricks.

Thus, there is an unmet need for non-invasive glucose monitoring (e.g.,monitoring glucose without drawing blood). The challenge has been that anon-invasive system requires adequate sensitivity and selectivity, alongwith repeatability of the results. Yet, this is a very large market,with an estimated annual market of over $10B in 2011 for self-monitoringof glucose levels.

One approach to non-invasive monitoring of blood constituents or bloodanalytes is to use near-infrared spectroscopy, such as absorptionspectroscopy or near-infrared diffuse reflection or transmissionspectroscopy. Some attempts have been made to use broadband lightsources, such as tungsten lamps, to perform the spectroscopy. However,several challenges have arisen in these efforts. First, many otherconstituents in the blood also have signatures in the near-infrared, sospectroscopy and pattern matching, often called spectral fingerprinting,is required to distinguish the glucose with sufficient confidence.Second, the non-invasive procedures have often transmitted or reflectedlight through the skin, but skin has many spectral artifacts in thenear-infrared that may mask the glucose signatures. Moreover, the skinmay have significant water and blood content. These difficulties becomeparticularly complicated when a weak light source is used, such as alamp. More light intensity can help to increase the signal levels, and,hence, the signal-to-noise ratio.

As described in this disclosure, by using brighter light sources, suchas fiber-based supercontinuum lasers, super-luminescent laser diodes,light-emitting diodes or a number of laser diodes, the near-infraredsignal level from blood constituents may be increased. By shining lightthrough the teeth, which have fewer spectral artifacts than skin in thenear-infrared, the blood constituents may be measured with lessinterfering artifacts. Also, by using pattern matching in spectralfingerprinting and various software techniques, the signatures fromdifferent constituents in the blood may be identified. Moreover,value-add services may be provided by wirelessly communicating themonitored data to a handheld device such as a smart phone, and thenwirelessly communicating the processed data to the cloud for storing,processing, and transmitting to several locations.

Dental care and the prevention of dental decay or dental caries haschanged in the United States over the past several decades, due to theintroduction of fluoride to drinking water, the use of fluoridedentifrices and rinses, application of topical fluoride in the dentaloffice, and improved dental hygiene. Despite these advances, dentaldecay continues to be the leading cause of tooth loss. With theimprovements over the past several decades, the majority of newlydiscovered carious lesions tend to be localized to the occlusal pits andfissures of the posterior dentition and the proximal contact sites.These early carious lesions may be often obscured in the complex andconvoluted topography of the pits and fissures or may be concealed bydebris that frequently accumulates in those regions of the posteriorteeth. Moreover, such lesions are difficult to detect in the earlystages of development.

Dental caries may be a dynamic disease that is characterized by toothdemineralization leading to an increase in the porosity of the enamelsurface. Leaving these lesions untreated may potentially lead tocavities reaching the dentine and pulp and perhaps eventually causingtooth loss. Occlusal surfaces (bite surfaces) and approximal surfaces(between the teeth) are among the most susceptible sites ofdemineralization due to acid attack from bacterial by-products in thebiofilm. Therefore, there is a need for detection of lesions at an earlystage, so that preventive agents may be used to inhibit or reverse thedemineralization.

Traditional methods for caries detection include visual examination andtactile probing with a sharp dental exploration tool, often assisted byradiographic (x-ray) imaging. However, detection using these methods maybe somewhat subjective; and, by the time that caries are evident undervisual and tactile examination, the disease may have already progressedto an advanced stage. Also, because of the ionizing nature of x-rays,they are dangerous to use (limited use with adults, and even less usedwith children). Although x-ray methods are suitable for approximalsurface lesion detection, they offer reduced utility for screening earlycaries in occlusal surfaces due to their lack of sensitivity at veryearly stages of the disease.

Some of the current imaging methods are based on the observation of thechanges of the light transport within the tooth, namely absorption,scattering, transmission, reflection and/or fluorescence of light.Porous media may scatter light more than uniform media. Taking advantageof this effect, the Fiber-optic trans-illumination is a qualitativemethod used to highlight the lesions within teeth by observing thepatterns formed when white light, pumped from one side of the tooth, isscattered away and/or absorbed by the lesion. This technique may bedifficult to quantify due to an uneven light distribution inside thetooth.

Another method called quantitative light-induced fluorescence—QLF—relieson different fluorescence from solid teeth and caries regions whenexcited with bright light in the visible. For example, when excited byrelatively high intensity blue light, healthy tooth enamel yields ahigher intensity of fluorescence than does demineralized enamel that hasbeen damaged by caries infection or any other cause. On the other hand,for excitation by relatively high intensity of red light, the oppositemagnitude change occurs, since this is the region of the spectrum forwhich bacteria and bacterial by-products in carious regions absorb andfluoresce more pronouncedly than do healthy areas. However, the imageprovided by QLF may be difficult to assess due to relatively poorcontrast between healthy and infected areas. Moreover, QLF may havedifficulty discriminating between white spots and stains because bothproduce similar effects. Stains on teeth are commonly observed in theocclusal sites of teeth, and this obscures the detection of caries usingvisible light.

As described in this disclosure, the near-infrared region of thespectrum offers a novel approach to imaging carious regions becausescattering is reduced and absorption by stains is low. For example, ithas been demonstrated that the scattering by enamel tissues reduces inthe form of 1/(wavelength)³, e.g., inversely as the cube of wavelength.By using a broadband light source in the short-wave infrared (SWIR) partof the spectrum, which corresponds approximately to 1400 nm to 2500 nm,lesions in the enamel and dentine may be observed. In one embodiment,intact teeth have low reflection over the SWIR wavelength range. In thepresence of caries, the scattering increases, and the scattering is afunction of wavelength; hence, the reflected signal decreases withincreasing wavelength. Moreover, particularly when caries exist in thedentine region, water build up may occur, and dips in the SWIR spectrumcorresponding to the water absorption lines may be observed. Thescattering and water absorption as a function of wavelength may thus beused for early detection of caries and for quantifying the degree ofdemineralization.

SWIR light may be generated by light sources such as lamps, lightemitting diodes, one or more laser diodes, super-luminescent laserdiodes, and fiber-based super-continuum sources. The SWIRsuper-continuum light sources advantageously may produce high intensityand power, as well as being a nearly transform-limited beam that mayalso be modulated. Also, apparatuses for caries detection may includeC-clamps over teeth, a handheld device with light input and lightdetection, which may also be attached to other dental equipment such asdrills. Alternatively, a mouth-guard type apparatus may be used tosimultaneously illuminate one or more teeth. Fiber optics may beconveniently used to guide the light to the patient as well as totransport the signal back to one or more detectors and receivers.

Remote sensing or hyper-spectral imaging often uses the sun forillumination, and the short-wave infrared (SWIR) windows of about1.5-1.8 microns and about 2-2.5 microns may be attractive because theatmosphere transmits in these wavelength ranges. Although the sun can bea bright and stable light source, its illumination may be affected bythe time-of-day variations in the sun angle as well as weatherconditions. For example, the sun may be advantageously used forapplications such as hyper-spectral imaging only between about 9 am to 3pm, and it may be difficult to use the sun during cloudy days or duringinclement weather. In one embodiment, the hyper-spectral sensors measurethe reflected solar signal at hundreds (e.g., 100 to 200+) contiguousand narrow wavelength bands (e.g., bandwidth between 5 nm and 10 nm).Hyper-spectral images may provide spectral information to identify anddistinguish between spectrally similar materials, providing the abilityto make proper distinctions among materials with only subtle signaturedifferences. In the SWIR wavelength range, numerous gases, liquids andsolids have unique chemical signatures, particularly materialscomprising hydro-carbon bonds, O—H bonds, N—H bonds, etc. Therefore,spectroscopy in the SWIR may be attractive for stand-off or remotesensing of materials based on their chemical signature, which maycomplement other imaging information.

A SWIR super-continuum (SC) source may be able to replace at least inpart the sun as an illumination source for active remote sensing,spectroscopy, or hyper-spectral imaging. In one embodiment, reflectedlight spectroscopy may be implemented using the SWIR light source, wherethe spectral reflectance can be the ratio of reflected energy toincident energy as a function of wavelength. Reflectance varies withwavelength for most materials because energy at certain wavelengths maybe scattered or absorbed to different degrees. Using a SWIR light sourcemay permit 24/7 detection of solids, liquids, or gases based on theirchemical signatures. As an example, natural gas leak detection andexploration may require the detection of methane and ethane, whoseprimary constituents include hydro-carbons. In the SWIR, for instance,methane and ethane exhibit various overtone and combination bands forvibrational and rotational resonances of hydro-carbons. In oneembodiment, diffuse reflection spectroscopy or absorption spectroscopymay be used to detect the presence of natural gas. The detection systemmay include a gas filter correlation radiometer, in a particularembodiment. Also, one embodiment of the SWIR light source may be anall-fiber integrated SWIR SC source, which leverages the maturetechnologies from the telecommunications and fiber optics industry.Beyond natural gas, active remote sensing in the SWIR may also be usedto identify other materials such as vegetation, greenhouse gases orenvironmental pollutants, soils and rocks, plastics, illicit drugs,counterfeit drugs, firearms and explosives, paints, and various buildingmaterials.

Counterfeiting of pharmaceuticals is a significant issue in thehealthcare community as well as for the pharmaceutical industryworldwide. For example, according to the World Health Organization, in2006 the market for counterfeit drugs worldwide was estimated at around$43 Billion. Moreover, the use of counterfeit medicines may result intreatment failure or even death. For instance, in 1995 dozens ofchildren in Haiti and Nigeria died after taking counterfeit medicinalsyrups that contained diethylene glycol, an industrial solvent. Asanother example, in Asia one report estimated that 90% of Viagra sold inShanghai, China, was counterfeit. With more pharmaceuticals beingpurchased through the internet, the problem of counterfeit drugs comingfrom across the borders into the United States has been growing rapidly.

A rapid, non-destructive, non-contact optical method for screening oridentification of counterfeit pharmaceuticals is needed. Spectroscopyusing near-infrared or short-wave infrared (SWIR) light may provide sucha method, because most pharmaceuticals comprise organic compounds thathave overtone or combination absorption bands in this wavelength range(e.g., between approximately 1-2.5 microns). Moreover, most drugpackaging materials are at least partially transparent in thenear-infrared or SWIR, so that drug compositions may be detected andidentified through the packaging non-destructively. Also, using anear-infrared or SWIR light source with a spatially coherent beampermits screening at stand-off or remote distances. Beyond identifyingcounterfeit drugs, the near-infrared or SWIR spectroscopy may have manyother beneficial applications. For example, spectroscopy may be used forrapid screening of illicit drugs or to implement process analyticaltechnology in pharmaceutical manufacturing. There are also a wide arrayof applications in assessment of quality in the food industry, includingscreening of fruit, vegetables, grains and meats.

In one embodiment, a near-infrared or SWIR super-continuum (SC) sourcemay be used as the light source for spectroscopy, active remote sensing,or hyper-spectral imaging. One embodiment of the SWIR light source maybe an all-fiber integrated SWIR SC source, which leverages the maturetechnologies from the telecommunications and fiber optics industry.Exemplary fiber-based super-continuum sources may emit light in thenear-infrared or SWIR between approximately 1.4-1.8 microns, 2-2.5microns, 1.4-2.4 microns, 1-1.8 microns, or any number of other bands.In particular embodiments, the detection system may be a dispersivespectrometer, a Fourier transform infrared spectrometer, or ahyper-spectral imaging detector or camera. In addition, reflection ordiffuse reflection light spectroscopy may be implemented using the SWIRlight source, where the spectral reflectance can be the ratio ofreflected energy to incident energy as a function of wavelength.

Breast cancer is considered to be the most common cancer among women inindustrialized countries. It is believed that early diagnosis andconsequent therapy could significantly reduce mortality. Mammography isconsidered the gold standard among imaging techniques in diagnosingbreast pathologies. However, the use of ionizing radiation inmammography may have adverse effects and lead to other complications.Moreover, screening x-ray mammography may be limited by false positivesand negatives, leading to unnecessary physical and psychologicalmorbidity. Although breast cancer is one of the focuses of thisdisclosure, the same techniques may also be applied to other cancertypes, including, for example, skin, prostate, brain, pancreatic, andcolorectal cancer.

Diagnostic methods for assessment and therapy follow-up of breast cancerinclude mammography, ultrasound, and magnetic resonance imaging. Themost effective screening technique at this time is x-ray mammography,with an overall sensitivity for breast cancer detection around 75%,which is even further reduced in women with dense breasts to around 62%.Moreover, x-ray mammography has a 22% false positive rate in women under50, and the method cannot accurately distinguish between benign andmalignant tumors. Magnetic resonance imaging and ultrasound aresometimes used to augment x-ray mammography, but they have limitationssuch as high cost, low throughput, limited specificity and lowsensitivity. Thus, there is a continued need to detect cancers earlierfor treatment, missed by mammography, and to add specificity to theprocedures.

Optical breast imaging may be an attractive technique for breast cancerto screen early, augment with mammography, or use in follow-ontreatments. Also, optical breast imaging may be performed by intrinsictissue contrast alone (e.g., hemoglobin, water, collagen, and lipidcontent), or with the use of exogenous fluorescent probes that targetspecific molecules. For example, near-infrared (NIR) light may be usedto assess optical properties, where the absorption and scattering by thetissue components may change with carcinoma. For most of the studiesconducted to date, NIR light in the wavelength range of 600-1000 nm hasbeen used for sufficient tissue penetration; these wavelengths havepermitted imaging up to several centimeters deep in soft tissue. Opticalbreast imaging using fluorescent contrast agents may improve lesioncontrast and may potentially permit detection of changes in breasttissue earlier. In one embodiment, the fluorescent probes may eitherbind specifically to certain targets associated with cancer or maynon-specifically accumulate at the tumor site.

Optical methods of imaging and spectroscopy can be non-invasive usingnon-ionizing electromagnetic radiation, and these techniques could beexploited for screening of wide populations and for therapy monitoring.“Optical mammography” may be a diffuse optical imaging technique thataims at detecting breast cancer, characterizing its physiological andpathological state, and possibly monitoring the efficacy of thetherapeutic treatment. The main constituents of breast tissue may belipid, collagen, water, blood, and other structural proteins. Theseconstituents may exhibit marked and characteristic absorption featuresin the NIR wavelength range. Thus, diffuse optical imaging andspectroscopy in the NIR may be helpful for diagnosing and monitoringbreast cancer. Another advantage of such imaging is that opticalinstruments tend to be portable and more cost effective as compared toother instrumentation that is conventionally used for medical diagnosis.This can be particularly true, if the mature technologies fortelecommunications and fiber optics are exploited.

Spectroscopy using NIR or short-wave infrared (SWIR) light may bebeneficial, because most tissue has organic compounds that have overtoneor combination absorption bands in this wavelength range (e.g., betweenapproximately 0.8-2.5 microns). In one embodiment, a NIR or SWIRsuper-continuum (SC) laser that is an all-fiber integrated source may beused as the light source for diagnosing cancerous tissue. Exemplaryfiber-based super-continuum sources may emit light in the NIR or SWIRbetween approximately 1.4-1.8 microns, 2-2.5 microns, 1.4-2.4 microns,1-1.8 microns, or any number of other bands. In particular embodiments,the detection system may be one or more photo-detectors, a dispersivespectrometer, a Fourier transform infrared spectrometer, or ahyper-spectral imaging detector or camera. In addition, reflection ordiffuse reflection light spectroscopy may be implemented using the SWIRlight source, where the spectral reflectance can be the ratio ofreflected energy to incident energy as a function of wavelength.

For breast cancer, experiments have shown that with growing cancer thecollagen content increases while the lipid content decreases. Therefore,early breast cancer detection may involve the monitoring of absorptionor scattering features from collagen and lipids. In addition, NIRspectroscopy may be used to determine the concentrations of hemoglobin,water, as well as oxygen saturation of hemoglobin and optical scatteringproperties in normal and cancerous breast tissue. For optical imaging tobe effective, it may also be desirable to select the wavelength rangethat leads to relatively high penetration depths into the tissue. In oneembodiment, it may be advantageous to use optical wavelengths in therange of about 1000-1400 nm. In another embodiment, it may beadvantageous to use optical wavelengths in the range of about 1600-1800nm. Higher optical power densities may be used to increase thesignal-to-noise ratio of the detected light through the diffusescattering tissue, and surface cooling or focused light may bebeneficial for preventing pain or damage to the skin and outer layersurrounding the breast tissue. Since optical energy may be non-ionizing,different exposure times may be used without danger or harmfulradiation.

SUMMARY

In one embodiment, a measurement system comprises an array of laserdiodes to operate in a pulsed mode and to generate light having one ormore optical wavelengths that includes at least one near-infraredwavelength. The array of laser diodes comprises one or more Braggreflectors, wherein at least a portion of the light generated by thearray is configured to penetrate tissue comprising skin. The measurementsystem further comprises a detection system comprising an infraredcamera and a first receiver comprising a plurality of detectors, whereinthe plurality of detectors comprises one or more detector arrays, andwherein the detection system is synchronized to the pulsing of the arrayof laser diodes. In addition, the detection system further comprises oneor more filters in front of at least a part of the detection system toselect some of the one of more optical wavelengths. The first receiveris configured to receive at least a first portion of light reflectedfrom the tissue from at least a part of the array of laser diodes, andwherein at least one of the plurality of detectors is coupled to one ormore analog-to-digital converters and a processor. Moreover, theinfrared camera is configured to receive at least a second portion oflight reflected from the tissue from the at least a part of the array oflaser diodes, wherein the infrared camera is configured to generate databased at least in part on the portion of the light received, and theinfrared camera is further coupled to the processor. A first lens systemis coupled to the plurality of detectors, and one or more lenses arecoupled to the infrared camera. The measurement system is configured togenerate an image using at least part of the data from the detectionsystem, the detection system is configured to non-invasively measureblood in blood vessels within or below a dermis layer within the skinbased at least in part on near-infrared diffuse reflection from theskin, and the detection system is configured to measure absorption ofhemoglobin in the near-infrared wavelength between 700 nanometers and1300 nanometers. Also, the processor is configured to compare theabsorption of hemoglobin between different spatial locations of tissue.Furthermore, the first receiver is configured to perform atime-of-flight measurement by measuring a time difference between thegenerated light from the array of laser diodes and the at least a firstportion of light reflected from the tissue from at least a part of thearray of laser diodes, and the measurement system is configured toreceive and process at least a portion of the time-of-flightmeasurement.

In another embodiment, a measurement system comprises an array of laserdiodes to operate in a pulsed mode and to generate light having one ormore optical wavelengths that includes at least one near-infraredwavelength. The array of laser diodes comprises one or more Braggreflectors, wherein the light from at least some of the laser diodes inthe array of laser diodes is spatially combined, and wherein at least aportion of the light generated by the array is configured to penetratetissue comprising skin. The measurement system further comprises adetection system comprising an infrared camera, wherein the detectionsystem is synchronized to the pulsing of the array of laser diodes, andwherein the detection system further comprises one or more filters infront of at least a part of the detection system to select some of theone of more optical wavelengths. The infrared camera is configured toreceive at least a first portion of light reflected from the tissue fromat least a part of the array of laser diodes, wherein a first lenssystem is coupled to the infrared camera, wherein the infrared camera isconfigured to generate data based at least in part on the portion of thelight received, and the infrared camera is further coupled to aprocessor. The measurement system is configured to generate an imageusing at least part of the data from the detection system. The detectionsystem is configured to non-invasively measure blood in blood vesselswithin or below a dermis layer within the skin based at least in part onnear-infrared diffuse reflection from the skin, and the detection systemis configured to measure absorption of hemoglobin in the near-infraredwavelength between 700 nanometers and 1300 nanometers. Furthermore, theprocessor is configured to compare the absorption of hemoglobin betweendifferent spatial locations of tissue. Moreover, the measurement systemis configured to measure one or more physiological parameters based atleast in part on the non-invasively measured blood within the tissue,wherein the one or more physiological parameters are generated at leastin part by using a Fourier transform of at least some of the at leastpart of the data from the detection system.

In yet another embodiment, a remote sensing system comprises an array oflaser diodes configured to generate light having an initial lightintensity and one or more optical wavelengths, wherein at least aportion of the one or more optical wavelengths is a near-infraredwavelength between 700 nanometers and 2500 nanometers. At least aportion of the array of laser diodes comprises one or more Braggreflectors, the at least a portion of the array of laser diodes isconfigured to be modulated, and wherein the light from at least some ofthe laser diodes in the array of laser diodes is spatially combined. Abeam splitter is configured to receive a portion of the light from thearray of laser diodes and to direct the portion of the light from thearray of laser diodes to an object, wherein the beam splitter isconfigured to separate the received portion of the light into aplurality of spatially separated lights. In addition, a detection systemcomprising a photodiode array is coupled to one or more lenses and oneor more spectral filters, as well as coupled to one or moreanalog-to-digital converters and a processor. The detection system isconfigured to receive at least a portion of light reflected from theobject, and the detection system is configured to be synchronized to theat least a portion of the array of laser diodes comprising Braggreflectors. Moreover, the detection system is further configured toperform a time-of-flight measurement, wherein the time-of-flightmeasurement comprises measuring a time difference between the generatedlight from the at least a portion of the array of laser diodes and theat least a portion of light reflected from the object. Furthermore, acamera system is coupled to a lens system and the processor, wherein thecamera system is further configured to capture one or more imagesincluding at least a part of the object. The remote sensing system isconfigured to generate a two-dimensional or three-dimensional mappingusing at least a portion of the one or more images and at least aportion of the time-of-flight measurement. Also, the remote sensingsystem is configured to improve signal-to-noise ratio of at least aportion of the two-dimensional or three-dimensional mapping byincreasing light intensity of the array of laser diodes relative to theinitial light intensity. Furthermore, the remote sensing system iscoupled to a smart phone or tablet, the smart phone or tablet comprisinga wireless receiver, a wireless transmitter, a display, a microphone, aspeaker, one or more buttons or knobs, a microprocessor and a touchscreen.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present disclosure, and forfurther features and advantages thereof, reference is now made to thefollowing description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 plots the transmittance versus wavenumber for glucose in themid-wave and long-wave infrared wavelengths between approximately 2.7 to12 microns.

FIG. 2 illustrates measurements of the absorbance of different bloodconstituents, such as glucose, hemoglobin, and hemoglobin A1c. Themeasurements are done using an FTIR spectrometer in samples with a 1 mmpath length.

FIG. 3A shows the normalized absorbance of water and glucose (not drawnto scale). Water shows transmission windows between about 1500-1850 nmand 2050-2500 nm.

FIG. 3B illustrates the absorbance of hemoglobin and oxygenatedhemoglobin overlapped with water.

FIG. 4A shows measured absorbance in different concentrations of glucosesolution over the wavelength range of about 2000 to 2400 nm. This datais collected using a SWIR super-continuum laser with the sample pathlength of about 1.1 mm.

FIG. 4B illustrates measured absorbance in different concentrations ofglucose solution over the wavelength range of about 1550 to 1800 nm. Thedata is collected using a SWIR super-continuum laser with a sample pathlength of about 10 mm.

FIG. 5 illustrates the spectrum for different blood constituents in thewavelength range of about 2 to 2.45 microns (2000 to 2450 nm).

FIG. 6 shows the transmittance versus wavelength in microns for theketone 3-hydroxybutyrate. The wavelength range is approximately 2 to 16microns.

FIG. 7 illustrates the optical absorbance for ketones as well as someother blood constituents in the wavelength range of about 2100 to 2400nm.

FIG. 8A shows the first derivative spectra of ketone and protein atconcentrations of 10 g/L (left). In addition, the first derivativespectra of urea, creatinine, and glucose are shown on the right atconcentrations of 10 g/L.

FIG. 8B illustrates the near infrared absorbance for triglyceride.

FIG. 8C shows the near-infrared reflectance spectrum for cholesterol.

FIG. 8D illustrates the near-infrared reflectance versus wavelength forvarious blood constituents, including cholesterol, glucose, albumin,uric acid, and urea.

FIG. 9 shows a schematic of the human skin. In particular, the dermismay comprise significant amounts of collagen, elastin, lipids, andwater.

FIG. 10 illustrates the absorption coefficients for water (includingscattering), adipose, collagen, and elastin.

FIG. 11 shows the dorsal of the hand, where a differential measurementmay be made to at least partially compensate for or subtract out theskin interference.

FIG. 12 shows the dorsal of the foot, where a differential measurementmay be made to at least partially compensate for or subtract out theskin interference.

FIG. 13 illustrates a typical human nail tissue structure and thecapillary vessels below it.

FIG. 14 shows the attenuation coefficient for seven nail samples thatare allowed to stand in an environment with a humidity level of 14%.These coefficients are measured using an FTIR spectrometer over thenear-infrared wavelength range of approximately 1 to 2.5 microns. Belowis also included the spectrum of glucose.

FIG. 15 illustrates the structure of a tooth.

FIG. 16A shows the attenuation coefficient for dental enamel and waterversus wavelength from approximately 600 nm to 2600 nm.

FIG. 16B illustrates the absorption spectrum of intact enamel anddentine in the wavelength range of approximately 1.2 to 2.4 microns.

FIG. 17 shows the near infrared spectral reflectance over the wavelengthrange of approximately 800 nm to 2500 nm from an occlusal tooth surface.The black diamonds correspond to the reflectance from a sound, intacttooth section. The asterisks correspond to a tooth section with anenamel lesion. The circles correspond to a tooth section with a dentinelesion.

FIG. 18A illustrates a clamp design of a human interface to cap over oneor more teeth and perform a non-invasive measurement of bloodconstituents.

FIG. 18B shows a mouth guard design of a human interface to perform anon-invasive measurement of blood constituents.

FIG. 19 illustrates a block diagram or building blocks for constructinghigh power laser diode assemblies.

FIG. 20 shows a platform architecture for different wavelength rangesfor an all-fiber-integrated, high powered, super-continuum light source.

FIG. 21 illustrates one embodiment of a short-wave infrared (SWIR)super-continuum (SC) light source.

FIG. 22 shows the output spectrum from the SWIR SC laser of FIG. 21 when˜10 m length of fiber for SC generation is used. This fiber is asingle-mode, non-dispersion shifted fiber that is optimized foroperation near 1550 nm.

FIG. 23 illustrates high power SWIR-SC lasers that may generate lightbetween approximately 1.4-1.8 microns (top) or approximately 2-2.5microns (bottom).

FIG. 24 schematically shows that the medical measurement device can bepart of a personal or body area network that communicates with anotherdevice (e.g., smart phone or tablet) that communicates with the cloud.The cloud may in turn communicate information with the user, healthcareproviders, or other designated recipients.

FIG. 25 illustrates the structure of a tooth.

FIG. 26A shows the attenuation coefficient for dental enamel and waterversus wavelength from approximately 600 nm to 2600 nm.

FIG. 26B illustrates the absorption spectrum of intact enamel anddentine in the wavelength range of approximately 1.2 to 2.4 microns.

FIG. 27 shows the near infrared spectral reflectance over the wavelengthrange of approximately 800 nm to 2500 nm from an occlusal tooth surface.The black diamonds correspond to the reflectance from a sound, intacttooth section. The asterisks correspond to a tooth section with anenamel lesion. The circles correspond to a tooth section with a dentinelesion.

FIG. 28 illustrates a hand-held dental tool design of a human interfacethat may also be coupled with other dental tools.

FIG. 29 illustrates a clamp design of a human interface to cap over oneor more teeth and perform a non-invasive measurement for dental caries.

FIG. 30 shows a mouth guard design of a human interface to perform anon-invasive measurement for dental caries.

FIG. 31 schematically shows that the medical measurement device can bepart of a personal or body area network that communicates with anotherdevice (e.g., smart phone or tablet) that communicates with the cloud.The cloud may in turn communicate information with the user, dental orhealthcare providers, or other designated recipients.

FIG. 32 illustrates wavelength bands for different chemical compoundsover the SWIR wavelength range of approximately 1400 nm to 2500 nm. Alsoindicated are whether the bands are overtone or combination bands.

FIG. 33A shows the absorption spectra for methane.

FIG. 33B shows the absorption spectra for ethane.

FIG. 34 illustrates the reflectance spectra for some members of thealkane family plus paraffin.

FIG. 35A depicts that micro-seepages may result from the verticalmovement of hydro-carbons from their respective reservoirs to thesurface. It is assumed that the rock column, including the seal rock,comprises interconnected fractures or micro-fracture systems.

FIG. 35B illustrates that surface alterations may occur because leakinghydro-carbons set up near-surface oxidation and/or reduction zones thatfavor the development of a diverse array of chemical and mineralogicalchanges.

FIG. 36A shows the reflectance spectra for locations with natural gasfields (3601) and locations without natural gas fields (3602).

FIG. 36B illustrates spectra from field tests over regions with naturalgas, which show two spectral features: one near 1.725 microns andanother doublet between about 2.311 microns and 2.36 microns.

FIG. 37 shows the reflectance spectra of a sample of oil emulsion fromthe Gulf of Mexico 2010 oil spill (different thicknesses of oil).

FIG. 38 illustrates the reflectance spectra of some representativeminerals that may be major components of rocks and soils.

FIG. 39 shows the reflectance spectra of different types of greenvegetation compared with dry, yellowed grass.

FIG. 40 illustrates the atmospheric absorption and scattering ofgreenhouse gases at different wavelengths.

FIG. 41 overlays the reflectance for different building materials fromthe ASTER spectra library.

FIG. 42 shows the absorbance for two common plastics, polyethylene andpolystyrene.

FIG. 43 shows the experimental set-up for a reflection-spectroscopybased stand-off detection system.

FIG. 44 illustrates the chemical structure and molecular formula forvarious explosives, along with the absorbance spectra obtained using asuper-continuum source.

FIG. 45A shows the reflection spectra for gypsum, pine wood, ammoniumnitrate and urea.

FIG. 45B illustrates the reflection spectra for three commercialautomotive paints and military grade CARC paint (chemical agentresistant coating) (reflectance in this case are in arbitrary units).

FIG. 46 shows the mid-wave infrared and long-wave infrared absorptionspectra for various illicit drugs. It is expected that overtone andcombination bands should be evident in the SWIR and near-infraredwavelength bands.

FIG. 47A is a schematic diagram of the basic elements of an imagingspectrometer.

FIG. 47B illustrates one example of a typical imaging spectrometer usedin hyper-spectral imaging systems.

FIG. 48 shows one example of a gas-filter correlation radiometer, whichis a detection system that uses a sample of the gas of interest as aspectral filter for the gas.

FIG. 49 exemplifies a dual-beam experimental set-up that may be used tosubtract out (or at least minimize the adverse effects of) light sourcefluctuations.

FIG. 50 shows the absorbance for two common plastics, polyethylene andpolystyrene.

FIG. 51 illustrates one example of the difference in near-infraredspectrum between an authentic tablet and a counterfeit tablet.

FIG. 52 shows the second derivative of the spectral comparison of Prozacand a similarly formulated generic.

FIG. 53 illustrates an example of the near infrared spectra fordifferent pure components of a studied drug.

FIG. 54 shows the mid-wave infrared and long-wave infrared absorptionspectra for various illicit drugs.

FIG. 55 shows the absorbance versus wavelength in the near-infraredregion for four classes of illegal drugs.

FIG. 56 illustrates the diffuse reflectance near-infrared spectrum ofheroin samples.

FIG. 57 illustrates the diffuse reflectance near-infrared spectra ofdifferent seized illicit drugs containing heroin of differentconcentrations, along with the spectrum for pure heroin.

FIG. 58A lists possible band assignments for the various spectralfeatures in pure heroin.

FIG. 58B also lists possible band assignments for the various spectralfeatures in pure heroin.

FIG. 59 shows the diffuse reflectance near-infrared spectra of differentcompounds that may be frequently employed as cutting agents.

FIG. 60 provides one example of a flow-chart in the process analyticaltechnology for the pharmaceutical industry.

FIG. 61 illustrates the typical near-infrared spectra of a variety ofexcipients.

FIG. 62 exemplifies the absorbance from the blending process of apharmaceutical compound.

FIG. 63 shows what might be an eventual flow-chart of a smartmanufacturing process.

FIG. 64A illustrates the near-infrared reflectance spectrum of wheatflour.

FIG. 64B shows the near-infrared absorbance spectra obtained indiffusion reflectance mode for a series of whole ‘Hass’ avocado fruit.

FIG. 65A is a schematic diagram of the basic elements of an imagingspectrometer.

FIG. 65B illustrates one example of a typical imaging spectrometer usedin hyper-spectral imaging systems.

FIG. 66 shows one example of the Fourier transform infraredspectrometer.

FIG. 67 exemplifies a dual-beam experimental set-up that may be used tosubtract out (or at least minimize the adverse effects of) light sourcefluctuations.

FIG. 68 illustrates the optical absorption of pure water, hemoglobinwithout oxygen, and hemoglobin saturated with oxygen.

FIG. 69 shows examples of various absorption bands of chemical speciesin the wavelength range between about 1200-2200 nm.

FIG. 70 depicts the structure of a female breast.

FIG. 71 illustrates particular embodiments of imaging systems foroptically scanning a breast.

FIG. 72 shows the normalized absorption spectra of main tissue absorbersin the NIR for breast cancer, between about 600-1100 nm.

FIG. 73 illustrates the normalized absorption coefficient in thewavelength range between about 500-1600 nm for many of the components ofbreast tissue.

FIG. 74A shows the typical spectra of the cancerous site of a treatedrat and the corresponding site of a normal rat and illustrates thelogarithm of the inverse of reflection spectra.

FIG. 74B shows the typical spectra of the cancerous site of a treatedrat and the corresponding site of a normal rat and illustrates secondderivative spectra.

FIG. 75 shows the second derivative of spectral changes over severalweeks between about 1600-1800 nm in rats with breast cancer.

FIG. 76 illustrates the second derivative spectra for cholesterol,collagen and elastin.

FIG. 77 shows the absorption coefficient as a function of wavelengthbetween about 1000 nm and 2600 nm for water, adipose and collagen.

FIG. 78 illustrates the absorbance for four types of collagen: collagenI, collagen II, collagen III, and collagen IV.

FIG. 79 shows an experimental set-up for testing chicken breast samplesusing collimated light. In this experiment, the collimated light has abeam diameter of about 3 mm.

FIG. 80 plots the measured depth of damage (in millimeters) versus thetime-averaged incident power (in Watts). Data is presented for laserwavelengths near 980 nm, 1210 nm and 1700 nm, and lines are drawncorresponding to penetration depths of approximately 2 mm, 3 mm, and 4mm.

FIG. 81 illustrates the optical absorption or density as a function ofwavelength between approximately 700 nm and 1300 nm for water,hemoglobin and oxygenated hemoglobin.

FIG. 82 shows a set-up used for in vitro damage experiments usingfocused infrared light. After a lens system, the tissue is placedbetween two microscope slides.

FIG. 83A presents histology of renal arteries comprising endothelium,media and adventitia layers and some renal nerves in or below theadventitia and illustrates renal arteries with no laser exposure.

FIG. 83B presents histology of renal arteries comprising endothelium,media and adventitia layers and some renal nerves in or below theadventitia and illustrates renal arteries after focused laser exposure,with the laser light near 1708 nm.

FIG. 84 illustrates the experimental set-up for ex vivo skin lasertreatment with surface cooling to protect the epidermis and top layer ofthe dermis.

FIG. 85A shows MTT histo-chemistry of ex vivo human skin treated with˜1708 nm laser and cold window (5 seconds precool; 2 mm diameter spotexposure for 3 seconds) at 725 mW corresponding to ˜70 J/cm2 averagefluence.

FIG. 85B also shows MTT histo-chemistry of ex vivo human skin treatedwith ˜1708 nm laser and cold window (5 seconds precool; 2 mm diameterspot exposure for 3 seconds) at 725 mW corresponding to ˜70 J/cm2average fluence.

FIG. 85C shows MTT histo-chemistry of ex vivo human skin treated with˜1708 nm laser and cold window (5 seconds precool; 2 mm diameter spotexposure for 3 seconds) at 830 mW corresponding to ˜80 J/cm2 averagefluence.

FIG. 85D also shows MTT histo-chemistry of ex vivo human skin treatedwith ˜1708 nm laser and cold window (5 seconds precool; 2 mm diameterspot exposure for 3 seconds) at 830 mW corresponding to ˜80 J/cm2average fluence.

DETAILED DESCRIPTION Section 1: Near-Infrared Lasers for Non-InvasiveMonitoring of Glucose, Ketones, Hba1C, and Other Blood Constituents

As required, detailed embodiments of the present disclosure aredescribed herein; however, it is to be understood that the disclosedembodiments are merely exemplary of the disclosure that may be embodiedin various and alternative forms. The figures are not necessarily toscale; some features may be exaggerated or minimized to show details ofparticular components. Therefore, specific structural and functionaldetails disclosed herein are not to be interpreted as limiting, butmerely as a representative basis for teaching one skilled in the art tovariously employ the present disclosure.

Various ailments or diseases may require measurement of theconcentration of one or more blood constituents. For example, diabetesmay require measurement of the blood glucose and HbA1c levels. On theother hand, diseases or disorders characterized by impaired glucosemetabolism may require the measurement of ketone bodies in the blood.Examples of impaired glucose metabolism diseases include Alzheimer's,Parkinson's, Huntington's, and Lou Gehrig's or amyotrophic lateralsclerosis (ALS). Techniques related to near-infrared spectroscopy orhyper-spectral imaging may be particularly advantageous for non-invasivemonitoring of some of these blood constituents.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. As used throughout this disclosure, the term “spectroscopy”means that a tissue or sample is inspected by comparing differentfeatures, such as wavelength (or frequency), spatial location,transmission, absorption, reflectivity, scattering, refractive index, oropacity. In one embodiment, “spectroscopy” may mean that the wavelengthof the light source is varied, and the transmission, absorption orreflectivity of the tissue or sample is measured as a function ofwavelength. In another embodiment, “spectroscopy” may mean that thewavelength dependence of the transmission, absorption or reflectivity iscompared between different spatial locations on a tissue or sample. Asan illustration, the “spectroscopy” may be performed by varying thewavelength of the light source, or by using a broadband light source andanalyzing the signal using a spectrometer, wavemeter, or opticalspectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium. In anotherembodiment, the mid-infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium or thulium. Inone embodiment, the “pump laser” may be a fiber laser, a solid statelaser, a laser involving a nonlinear crystal, an optical parametricoscillator, a semiconductor laser, or a plurality of semiconductorlasers that may be multiplexed together. In another embodiment, the“pump laser” may be coupled to the gain medium by using a fiber coupler,a dichroic mirror, a multiplexer, a wavelength division multiplexer, agrating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth of at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, the Ramaneffect, modulational instability, and self-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

Spectrum for Glucose

One molecule of interest is glucose. The glucose molecule has thechemical formula C6H12O6, so it has a number of hydro-carbon bonds. Anexample of the infrared transmittance of glucose 100 is illustrated inFIG. 1. The vibrational spectroscopy shows that the strongest lines forbending and stretching modes of C—H and O—H bonds lie in the wavelengthrange of approximately 6-12 microns. However, light sources anddetectors are more difficult in the mid-wave infrared and long-waveinfrared, and there is also strongly increasing water absorption in thehuman body beyond about 2.5 microns. Although weaker, there are alsonon-linear combinations of stretching and bending modes between about 2to 2.5 microns, and first overtone of C—H stretching modes betweenapproximately 1.5-1.8 microns. These signatures may fall in valleys ofwater absorption, permitting non-invasive detection through the body. Inaddition, there are yet weaker features from the second overtones andhigher-order combinations between about 0.8-1.2 microns; in addition tobeing weaker, these features may also be masked by absorption in thehemoglobin. Hence, the short-wave infrared (SWIR) wavelength range ofapproximately 1.4 to 2.5 microns may be an attractive window fornear-infrared spectroscopy of blood constituents.

As an example, measurements of the optical absorbance 200 of hemoglobin,glucose and HbA1c have been performed using a Fourier-Transform InfraredSpectrometer—FTIR. As FIG. 2 shows, in the SWIR wavelength rangehemoglobin is nearly flat in spectrum 201 (the noise at the edges is dueto the weaker light signal in the measurements). On the other hand, theglucose absorbance 202 has at least five distinct peaks near 1587 nm,1750 nm, 2120 nm, 2270 nm and 2320 nm.

FIG. 3A overlaps 300 the normalized absorbance of glucose 301 with theabsorbance of water 302 (not drawn to scale). It may be seen that waterhas an absorbance feature between approximately 1850 nm and 2050 nm, butwater 302 also has a nice transmission window between approximately1500-1850 nm and 2050 to 2500 nm. For wavelengths less than about 1100nm, the absorption of hemoglobin 351 and oxygenated hemoglobin 352 inFIG. 3B has a number of features 350, which may make it more difficultto measure blood constituents. Also, beyond 2500 nm the water absorptionbecomes considerably stronger over a wide wavelength range. Therefore,an advantageous window for measuring glucose and other bloodconstituents may be in the SWIR between 1500 and 1850 nm and 2050 to2500 nm. These are exemplary wavelength ranges, and other ranges can beused that would still fall within the scope of this disclosure.

One further consideration in choosing the laser wavelength is known asthe “eye safe” window for wavelengths longer than about 1400 nm. Inparticular, wavelengths in the eye safe window may not transmit down tothe retina of the eye, and therefore, these wavelengths may be lesslikely to create permanent eye damage. The near-infrared wavelengthshave the potential to be dangerous, because the eye cannot see thewavelengths (as it can in the visible), yet they can penetrate and causedamage to the eye. Even if a practitioner is not looking directly at thelaser beam, the practitioner's eyes may receive stray light from areflection or scattering from some surface. Hence, it can always be agood practice to use eye protection when working around lasers. Sincewavelengths longer than about 1400 nm are substantially not transmittedto the retina or substantially absorbed in the retina, this wavelengthrange is known as the eye safe window. For wavelengths longer than 1400nm, in general only the cornea of the eye may receive or absorb thelight radiation.

Beyond measuring blood constituents such as glucose using FTIRspectrometers, measurements have also been conducted in anotherembodiment using super-continuum lasers, which will be described laterin this disclosure. In this particular embodiment, some of the exemplarypreliminary data for glucose absorbance are illustrated in FIGS. 4A and4B. The optical spectra 401 in FIG. 4A for different levels of glucoseconcentration in the wavelength range between 2000 and 2400 nm show thethree absorption peaks near 2120 nm (2.12 μm), 2270 nm (2.27 μm) and2320 nm (2.32 μm). Moreover, the optical spectra 402 in FIG. 4B fordifferent levels of glucose concentration in the wavelength rangebetween 1500 and 1800 nm show the two broader absorption peaks near 1587nm and 1750 nm. It should be appreciated that although data measuredwith FTIR spectrometers or super-continuum lasers have been illustrated,other light sources can also be used to obtain the data, such assuper-luminescent laser diodes, light emitting diodes, a plurality oflaser diodes, or even bright lamp sources that generate adequate lightin the SWIR.

Although glucose has a distinctive signature in the SWIR wavelengthrange, one problem of non-invasive glucose monitoring is that many otherblood constituents also have hydro-carbon bonds. Consequently, there canbe interfering signals from other constituents in the blood. As anexample, FIG. 5 illustrates the spectrum 500 for different bloodconstituents in the wavelength range of 2 to 2.45 microns. The glucoseabsorption spectrum 501 can be unique with its three peaks in thiswavelength range. However, other blood constituents such as triacetin502, ascorbate 503, lactate 504, alanine 505, urea 506, and BSA 507 alsohave spectral features in this wavelength range. To distinguish theglucose 501 from these overlapping spectra, it may be advantageous tohave information at multiple wavelengths. In addition, it may beadvantageous to use pattern matching algorithms and other software andmathematical methods to identify the blood constituents of interest. Inone embodiment, the spectrum may be correlated with a library of knownspectra to determine the overlap integrals, and a threshold function maybe used to quantify the concentration of different constituents. This isjust one way to perform the signal processing, and many othertechniques, algorithms, and software may be used and would fall withinthe scope of this disclosure.

Ketone Bodies Monitoring

Beyond glucose, there are many other blood constituents that may also beof interest for health or disease monitoring. In another embodiment, itmay be desirous to monitor the level of ketone bodies in the bloodstream. Ketone bodies are three water-soluble compounds that areproduced as by-products when fatty acids are broken down for energy inthe liver. Two of the three are used as a source of energy in the heartand brain, while the third is a waste product excreted from the body. Inparticular, the three endogenous ketone bodies are acetone, acetoaceticacid, and beta-hydroxybutyrate or 3-hydroxybutyrate, and the wasteproduct ketone body is acetone.

Ketone bodies may be used for energy, where they are transported fromthe liver to other tissues. The brain may utilize ketone bodies whensufficient glucose is not available for energy. For instance, this mayoccur during fasting, strenuous exercise, low carbohydrate, ketogenicdiet and in neonates. Unlike most other tissues that have additionalenergy sources such as fatty acids during periods of low blood glucose,the brain cannot break down fatty acids and relies instead on ketones.In one embodiment, these ketone bodies are detected.

Ketone bodies may also be used for reducing or eliminating symptoms ofdiseases or disorders characterized by impaired glucose metabolism. Forexample, diseases associated with reduced neuronal metabolism of glucoseinclude Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis (ALS, also called Lou Gehrig's disease), Huntington's diseaseand epilepsy. In one embodiment, monitoring of alternate sources ofketone bodies that may be administered orally as a dietary supplement orin a nutritional composition to counteract some of the glucosemetabolism impairments is performed. However, if ketone bodiessupplements are provided, there is also a need to monitor the ketonelevel in the blood stream. For instance, if elevated levels of ketonebodies are present in the body, this may lead to ketosis; hyperketonemiais also an elevated level of ketone bodies in the blood. In addition,both acetoacetic acid and beta-hydroxybutyric acid are acidic, and, iflevels of these ketone bodies are too high, the pH of the blood maydrop, resulting in ketoacidosis.

The general formula for ketones is CnH2n0. In organic chemistry, aketone is an organic compound with the structure RC(═O)R′, where R andR′ can be a variety of carbon-containing substituents. It features acarbonyl group (C═O) bonded to two other carbon atoms. Because theketones contain the hydrocarbon bonds, there might be expected to befeatures in the SWIR, similar in structure to those found for glucose.

The infrared spectrum 600 for the ketone 3-hydroxybutyrate isillustrated in FIG. 6. Just as in glucose, there are significantfeatures in the mid- and long-wave infrared between 6 to 12 microns, butthese may be difficult to observe non-invasively. On the other hand,there are some features in the SWIR that may be weaker, but they couldpotentially be observed non-invasively, perhaps through blood and water.

The optical spectra 700 for ketones as well as some other bloodconstituents are exemplified in FIG. 7 in the wavelength range of 2100nm to 2400 nm. In this embodiment, the absorbance for ketones is 701,while the absorbance for glucose is 702. However, there are alsofeatures in this wavelength range for other blood constituents, such asurea 703, albumin or blood protein 704, creatinine 705, and nitrite 706.In this wavelength range of 2100 to 2400 nm, the features for ketone 701seem more spectrally pronounced than even glucose.

Different signal processing techniques can be used to enhance thespectral differences between different constituents. In one embodiment,the first or second derivatives of the spectra may enable betterdiscrimination between substances. The first derivative may help removeany flat offset or background, while the second derivative may help toremove any sloped offset or background. In some instances, the first orsecond derivative may be applied after curve fitting or smoothing thereflectance, transmittance, or absorbance. For example, FIG. 8Aillustrates the derivative spectra for ketone 801 and glucose 802, whichcan be distinguished from the derivative spectra for protein 803, urea804 and creatinine 805. Based on FIG. 8A, it appears that ketones 801may have a more pronounced difference than even glucose 802 in thewavelength range between 2100 and 2400 nm. Therefore, ketone bodiesshould also be capable of being monitored using a non-invasive opticaltechnique in the SWIR, and a different pattern matching library could beused for glucose and ketones.

Hemoglobin A1C Monitoring

Another blood constituent that may be of interest for monitoring ofhealth or diseases is hemoglobin A1c, also known as HbA1c or glycatedhemoglobin (glycol-hemoglobin or glycosylated hemoglobin). HbA1c is aform of hemoglobin that is measured primarily to identify the averageplasma glucose concentration over prolonged periods of time. Thus, HbA1cmay serve as a marker for average blood glucose levels over the previousmonths prior to the measurements.

In one embodiment, when a physician suspects that a patient may bediabetic, the measurement of HbA1c may be one of the first tests thatare conducted. An HbA1c level less than approximately 6% may beconsidered normal. On the other hand, an HbA1c level greater thanapproximately 6.5% may be considered to be diabetic. In diabetesmellitus, higher amounts of HbA1c indicate poorer control of bloodglucose levels. Thus, monitoring the HbA1c in diabetic patients mayimprove treatment. Current techniques for measuring HbA1c requiredrawing blood, which may be inconvenient and painful. The point-of-caredevices use immunoassay or boronate affinity chromatography, as anexample. Thus, there is also an unmet need for non-invasive monitoringof HbA1c.

FIG. 2 illustrates the FTIR measurements of HbA1c absorbance 203 overthe wavelength range between 1500 and 2400 nm for a concentration ofapproximately 1 mg/ml. Whereas the absorbance of hemoglobin 201 overthis wavelength range is approximately flat, the HbA1c absorbance 203shows broad features and distinct curvature. Although the HbA1cabsorbance 203 does not appear to exhibit as pronounced features asglucose 202, the non-invasive SWIR measurement should be able to detectHbA1c with appropriate pattern matching algorithms. Moreover, thespectrum for HbA1c may be further enhanced by using first or secondderivative data, as seen for ketones in FIG. 8A. Beyond absorption,reflectance, or transmission spectroscopy, it may also be possible todetect blood constituents such as HbA1c using Raman spectroscopy orsurface-enhanced Raman spectroscopy. In general, Raman spectroscopy mayrequire higher optical power levels.

As an illustration, non-invasive measurement of blood constituents suchas glucose, ketone bodies, and HbA1c has been discussed thus far.However, other blood constituents can also be measured using similartechniques, and these are also intended to be covered by thisdisclosure. In other embodiments, blood constituents such as proteins,albumin, urea, creatinine or nitrites could also be measured. Forinstance, the same type of SWIR optical techniques might be used, butthe pattern matching algorithms and software could use different libraryfeatures or functions for the different constituents.

In yet another embodiment, the optical techniques described in thisdisclosure could also be used to measure levels of triglycerides.Triglycerides are bundles of fats that may be found in the blood stream,particularly after ingesting meals. The body manufactures triglyceridesfrom carbohydrates and fatty foods that are eaten. In other words,triglycerides are the body's storage form of fat. Triglycerides arecomprised of three fatty acids attached to a glycerol molecule, andmeasuring the level of triglycerides may be important for diabetics. Thetriglyceride levels or concentrations in blood may be rated as follows:desirable or normal may be less than 150 mg/dl; borderline high may be150-199 mg/dl; high may be 200-499 mg/dl; and very high may be 500 mg/dlor greater. FIG. 8B illustrates one example of the near-infraredabsorbance 825 for triglycerides. There are distinct absorbance peaks inthe spectrum that should be measurable. The characteristic absorptionbands may be assigned as follows: (a) the first overtones of C—Hstretching vibrations (1600-1900 nm); (b) the region of second overtonesof C—H stretching vibrations (1100-1250 nm); and, (c) two regions(2000-2200 nm and 1350-1500 nm) that comprise bands due to combinationsof C—H stretching vibrations and other vibrational modes.

A further example of blood compositions that can be detected or measuredusing near-infrared light includes cholesterol monitoring. For example,FIG. 8C shows the near-infrared reflectance spectrum for cholesterol 850with wavelength in microns (μm). Distinct absorption peaks areobservable near 1210 nm (1.21 μm), 1720 nm (1.72 μm), and between2300-2500 nm (2.3-2.5 μm). Also, there are other features near 1450 nm(1.45 μm) and 2050 nm (2.05 μm). In FIG. 8D the near-infraredreflectances 875 are displayed versus wavelength (nm) for various bloodconstituents. The spectrum for cholesterol 876 is overlaid with glucose877, albumin 878, uric acid 879, and urea 880. As may be noted from FIG.8D, at about 1720 nm and 2300 nm, cholesterol 876 reaches approximatereflectance peaks, while some of the other analytes are in a moregradual mode. Various signal processing methods may be used to identifyand quantify the concentration of cholesterol 876 and/or glucose 877, orsome of the other blood constituents.

As illustrated by FIGS. 5 and 7, one of the issues in measuring aparticular blood constituent is the interfering and overlapping signalfrom other blood constituents. The selection of the constituent ofinterest may be improved using a number of techniques. For example, ahigher light level or intensity may improve the signal-to-noise ratiofor the measurement. Second, mathematical modeling and signal processingmethodologies may help to reduce the interference, such as multivariatetechniques, multiple linear regression, and factor-based algorithms, forexample. For instance, a number of mathematical approaches includemultiple linear regression, partial least squares, and principalcomponent regression (PCR). Also, as illustrated in FIG. 8A, variousmathematical derivatives, including the first and second derivatives,may help to accentuate differences between spectra. In addition, byusing a wider wavelength range and using more sampling wavelengths mayimprove the ability to discriminate one signal from another. These arejust examples of some of the methods of improving the ability todiscriminate between different constituents, but other techniques mayalso be used and are intended to be covered by this disclosure.

Interference from Skin

Several proposed non-invasive glucose monitoring techniques rely ontransmission, absorption, and/or diffuse reflection through the skin tomeasure blood constituents or blood analytes in veins, arteries,capillaries or in the tissue itself. However, on top of the interferencefrom other blood constituents or analytes, the skin also introducessignificant interference. For example, chemical, structural, andphysiological variations occur that may produce relatively large andnonlinear changes in the optical properties of the tissue sample. In oneembodiment, the near-infrared reflectance or absorbance spectrum may bea complex combination of the tissue scattering properties that resultfrom the concentration and characteristics of a multiplicity of tissuecomponents including water, fat, protein, collagen, elastin, and/orglucose. Moreover, the optical properties of the skin may also changewith environmental factors such as humidity, temperature and pressure.Physiological variation may also cause changes in the tissue measurementover time and may vary based on lifestyle, health, aging, etc. Thestructure and composition of skin may also vary widely amongindividuals, between different sites within an individual, and over timeon the same individual. Thus, the skin introduces a dynamic interferencesignal that may have a wide variation due to a number of parameters.

FIG. 9 shows a schematic cross-section of human skin 900, 901. The toplayer of the skin is epidermis 902, followed by a layer of dermis 903and then subcutaneous fat 904 below the dermis. The epidermis 902, witha thickness of approximately 10-150 microns, may provide a barrier toinfection and loss of moisture and other body constituents. The dermis903 ranges in thickness from approximately 0.5 mm to 4 mm (averagesapproximately 1.2 mm over most of the body) and may provide themechanical strength and elasticity of skin.

In the dermis 903, water may account for approximately 70% of thevolume. The next most abundant constituent in the dermis 903 may becollagen 905, a fibrous protein comprising 70-75% of the dry weight ofthe dermis 903. Elastin fibers 906, also a protein, may also beplentiful in the dermis 903, although they constitute a smaller portionof the bulk. In addition, the dermis 903 may contain a variety ofstructures (e.g., sweat glands, hair follicles with adipose richsebaceous glands 907 near their roots, and blood vessels) and othercellular constituents.

Below the dermis 903 lies the subcutaneous layer 904 comprising mostlyadipose tissue. The subcutaneous layer 904 may be by volumeapproximately 10% water and may be comprised primarily of cells rich intriglycerides or fat. With this complicated structure of the skin900,901, the concentration of glucose may vary in each layer accordingto a variety of factors including the water content, the relative sizesof the fluid compartments, the distribution of capillaries, theperfusion of blood, the glucose uptake of cells, the concentration ofglucose in blood, and the driving forces (e.g., osmotic pressure) behinddiffusion.

To better understand the interference that the skin introduces whenattempting to measure glucose, the absorption coefficient for thevarious skin constituents should be examined. For example, FIG. 10illustrates 1000 the absorption coefficients for water (includingscattering) 1001, adipose 1002, collagen 1003 and elastin 1004. Notethat the absorption curves for water 1001 and adipose 1002 arecalibrated, whereas the absorption curves for collagen 1003 and elastin1004 are in arbitrary units. Also shown are vertical lines demarcatingthe wavelengths near 1210 nm 1005 and 1720 nm 1006. In general, thewater absorption increases with increasing wavelength. With theincreasing absorption beyond about 2000 nm, it may be difficult toachieve deeper penetration into biological tissue in the infraredwavelengths beyond approximately 2500 nm.

Although the absorption coefficient may be useful for determining thematerial in which light of a certain infrared wavelength will beabsorbed, to determine the penetration depth of the light of a certainwavelength may also require the addition of scattering loss to thecurves. For example, the water curve 1001 includes the scattering losscurve in addition to the water absorption. In particular, the scatteringloss can be significantly higher at shorter wavelengths. In oneembodiment, near the wavelength of 1720 nm (vertical line 1006 shown inFIG. 10), the adipose absorption 1002 can still be higher than the waterplus scattering loss 1001. For tissue that contains adipose, collagenand elastin, such as the dermis of the skin, the total absorption canexceed the light energy lost to water absorption and light scattering at1720 nm. On the other hand, at 1210 nm the adipose absorption 1002 canbe considerably lower than the water plus scattering loss 1001,particularly since the scattering loss can be dominant at these shorterwavelengths.

The interference for glucose lines observed through skin may beillustrated by overlaying the glucose lines over the absorption curves1000 for the skin constituents. For example, FIG. 2 illustrated that theglucose absorption 202 included features centered around 1587 nm, 1750nm, 2120 nm, 2270 nm and 2320 nm. On FIG. 10 vertical lines have beendrawn at the glucose line wavelengths of 1587 nm 1007, 1750 nm 1008,2120 nm 1009, 2270 nm 1010 and 2320 nm 1011. In one embodiment, it maybe difficult to detect the glucose lines near 1750 nm 1008, 2270 nm 1010and 2320 nm 1011 due to significant spectral interference from otherskin constituents. On the other hand, the glucose line near 1587 m 1007may be more easily detected because it peaks while most of the otherskin constituents are sloped downward toward an absorption valley.Moreover, the glucose line near 2120 nm 1009 may also be detectable forsimilar reasons, although adipose may have conflicting behavior due tolocal absorption minimum and maximum nearby in wavelength.

Thus, beyond the problem of other blood constituents or analytes havingoverlapping spectral features (e.g., FIG. 5), it may be difficult toobserve glucose spectral signatures through the skin and itsconstituents of water, adipose, collagen and elastin. One approach toovercoming this difficulty may be to try to measure the bloodconstituents in veins that are located at relatively shallow distancesbelow the skin. Veins may be more beneficial for the measurement thanarteries, since arteries tend to be located at deeper levels below theskin. Also, in one embodiment it may be advantageous to use adifferential measurement to subtract out some of the interferingabsorption lines from the skin. For example, an instrument head may bedesigned to place one probe above a region of skin over a blood vein,while a second probe may be placed at a region of the skin without anoticeable blood vein below it. Then, by differencing the signals fromthe two probes, at least part of the skin interference may be cancelledout.

Two representative embodiments for performing such a differentialmeasurement are illustrated in FIG. 11 and FIG. 12. In one embodimentshown in FIG. 11, the dorsal of the hand 1100 may be used for measuringblood constituents or analytes. The dorsal of the hand 1100 may haveregions that have distinct veins 1101 as well as regions where the veinsare not as shallow or pronounced 1102. By stretching the hand andleaning it backwards, the veins 1101 may be accentuated in some cases. Anear-infrared diffuse reflectance measurement may be performed byplacing one probe 1103 above the vein-rich region 1101. To turn thisinto a differential measurement, a second probe 1104 may be placed abovea region without distinct veins 1102. Then, the outputs from the twoprobes may be subtracted 1105 to at least partially cancel out thefeatures from the skin. The subtraction may be done preferably in theelectrical domain, although it can also be performed in the opticaldomain or digitally/mathematically using sampled data based on theelectrical and/or optical signals. Although one example of using thedorsal of the hand 1100 is shown, many other parts of the hand can beused within the scope of this disclosure. For example, alternate methodsmay use transmission through the webbing between the thumb and thefingers 1106, or transmission or diffuse reflection through the tips ofthe fingers 1107.

In another embodiment, the dorsal of the foot 1200 may be used insteadof the hand. One advantage of such a configuration may be that forself-testing by a user, the foot may be easier to position theinstrument using both hands. One probe 1203 may be placed over regionswhere there are more distinct veins 1201, and a near-infrared diffusereflectance measurement may be made. For a differential measurement, asecond probe 1204 may be placed over a region with less prominent veins1202, and then the two probe signals may be subtracted, eitherelectronically or optically, or may be digitized/sampled and processedmathematically depending on the particular application andimplementation. As with the hand, the differential measurements may beintended to compensate for or subtract out (at least in part) theinterference from the skin. Since two regions are used in closeproximity on the same body part, this may also aid in removing somevariability in the skin from environmental effects such as temperature,humidity, or pressure. In addition, it may be advantageous to firsttreat the skin before the measurement, by perhaps wiping with a cloth ortreated cotton ball, applying some sort of cream, or placing an ice cubeor chilled bag over the region of interest.

Although two embodiments have been described, many other locations onthe body may be used using a single or differential probe within thescope of this disclosure. In yet another embodiment, the wrist may beadvantageously used, particularly where a pulse rate is typicallymonitored. Since the pulse may be easily felt on the wrist, there isunderlying the region a distinct blood flow. Other embodiments may useother parts of the body, such as the ear lobes, the tongue, the innerlip, the nails, the eye, or the teeth. Some of these embodiments will befurther described below. The ear lobes or the tip of the tongue may beadvantageous because they are thinner skin regions, thus permittingtransmission rather than diffuse reflection. However, the interferencefrom the skin is still a problem in these embodiments. Other regionssuch as the inner lip or the bottom of the tongue may be contemplatedbecause distinct veins are observable, but still the interference fromthe skin may be problematic in these embodiments. The eye may seem as aviable alternative because it is more transparent than skin. However,there are still issues with scattering in the eye. For example, theanterior chamber of the eye (the space between the cornea and the iris)comprises a fluid known as aqueous humor. However, the glucose level inthe eye chamber may have a significant temporal lag on changes in theglucose level compared to the blood glucose level.

Because of the complexity of the interference from skin in non-invasiveglucose monitoring (e.g., FIG. 10), other parts of the body without skinabove blood vessels or capillaries may be alternative candidates formeasuring blood constituents. One embodiment may involve transmission orreflection through human nails. As an example, FIG. 13 illustrates atypical human nail tissue structure 1300 and the capillary vessels belowit. The fingernail 1301 is approximately 1 mm thick, and below thisresides a layer of epidermis 1302 with a thickness of approximately 1mm. The dermis 1304 is also shown, and within particularly the top about0.5 mm of dermis are a significant number of capillary vessels. Tomeasure the blood constituents, the light exposed on the top of thefingernail must penetrate about 2-2.5 mm or more, and the reflectedlight (round trip passage) should be sufficiently strong to measure. Inone embodiment, the distance required to penetrate could be reduced bydrilling a hole in the fingernail 1301.

In this alternative embodiment using the fingernail, there may still beinterference from the nail's spectral features. For example, FIG. 14illustrates the attenuation coefficient 1400 for seven nail samples thatare allowed to stand in an environment with a humidity level of 14%.These coefficients are measured using an FTIR spectrometer over thenear-infrared wavelength range of approximately 1 to 2.5 microns. Thesespectra are believed to correspond to the spectra of keratin containedin the nail plate. The base lines for the different samples are believedto differ because of the influence of scattering. Several of theabsorption peaks observed correspond to peaks of keratin absorption,while other features may appear from the underlying epidermis anddermis. It should also be noted that the attenuation coefficients 1400also vary considerably depending on humidity level or water content aswell as temperature and other environmental factors. Moreover, theattenuation coefficient may also change in the presence of nail polishof various sorts.

Similar to skin, the large variations in attenuation coefficient forfingernails also may interfere with the absorption peaks of glucose. Asan example, in FIG. 14 below the fingernail spectrum is also shown theglucose spectrum 1401 for two different glucose concentrations. Thevertical lines 1402, 1403, 1404, 1405 and 1406 are drawn to illustratethe glucose absorption peaks and where they lie on the fingernailspectra 1400. As is apparent, the nail has interfering features that maybe similar to skin, particularly since both have spectra that vary notonly in wavelength but also with environmental factors. In oneembodiment, it may be possible to see the glucose peaks 1402 and 1404through the fingernail, but it may be much more difficult to observe theglucose peaks near 1403, 1405 and 1406.

Transmission or Reflection Through Teeth

Yet another embodiment may observe the transmittance or reflectancethrough teeth to measure blood constituents or analytes. FIG. 15illustrates an exemplary structure of a tooth 1500. The tooth 1500 has atop layer called the crown 1501 and below that a root 1502 that reacheswell into the gum 1506 and bone 1508 of the mouth. The exterior of thecrown 1501 is an enamel layer 1503, and below the enamel is a layer ofdentine 1504 that sits atop a layer of cementum 1507. Below the dentine1504 is a pulp region 1505, which comprises within it blood vessels 1509and nerves 1510. If the light can penetrate the enamel 1503 and dentine1504, then the blood flow and blood constituents can be measured throughthe blood vessels in the dental pulp 1505. While it may be true that theamount of blood flow in the dental pulp 1505 may be less since itcomprises capillaries, the smaller blood flow could still beadvantageous if there is less interfering spectral features from thetooth.

The transmission, absorption and reflection from teeth has been studiedin the near infrared, and, although there are some features, the enameland dentine appear to be fairly transparent in the near infrared(particularly wavelengths between 1500 and 2500 nm). For example, theabsorption or extinction ratio for light transmission has been studied.FIG. 16A illustrates the attenuation coefficient 1600 for dental enamel1601 (filled circles) and the absorption coefficient of water 1602 (opencircles) versus wavelength. Near-infrared light may penetrate muchfurther without scattering through all the tooth enamel, due to thereduced scattering coefficient in normal enamel. Scattering in enamelmay be fairly strong in the visible, but decreases as approximately1/(wavelength)3 [i.e., inverse of the cube of the wavelength] withincreasing wavelength to a value of only 2-3 cm−1 at 1310 nm and 1550 nmin the near infrared. Therefore, enamel may be virtually transparent inthe near infrared with optical attenuation 1-2 orders of magnitude lessthan in the visible range.

As another example, FIG. 16B illustrates the absorption spectrum 1650 ofintact enamel 1651 (dashed line) and dentine 1652 (solid line) in thewavelength range of approximately 1.2 to 2.4 microns. In the nearinfrared there are two absorption bands around 1.5 and 2 microns. Theband with a peak around 1.57 microns may be attributed to the overtoneof valent vibration of water present in both enamel and dentine. In thisband, the absorption is greater for dentine than for enamel, which maybe related to the large water content in this tissue. In the region of 2microns, dentine may have two absorption bands, and enamel one. The bandwith a maximum near 2.1 microns may belong to the overtone of vibrationof PO hydroxyapatite groups, which is the main substance of both enameland dentine. Moreover, the band with a peak near 1.96 microns in dentinemay correspond to water absorption (dentine may contain substantiallyhigher water than enamel).

In addition to the absorption coefficient, the reflectance from intactteeth and teeth with dental caries (e.g., cavities) has been studied. Inone embodiment, FIG. 17 shows the near infrared spectral reflectance1700 over the wavelength range of approximately 800 nm to 2500 nm froman occlusal (e.g., top/bottom) tooth surface 1704. The curve with blackdiamonds 1701 corresponds to the reflectance from a sound, intact toothsection. The curve with asterisks*1702 corresponds to a tooth sectionwith an enamel lesion. The curve with circles 1703 corresponds to atooth section with a dentine lesion. Thus, when there is a lesion, morescattering occurs and there may be an increase in the reflected light.

For wavelengths shorter than approximately 1400 nm, the shapes of thespectra remain similar, but the amplitude of the reflection changes withlesions. Between approximately 1400 nm and 2500 nm, an intact tooth 1701has low reflectance (e.g., high transmission), and the reflectanceappears to be more or less independent of wavelength. On the other hand,in the presence of lesions 1702 and 1703, there is increased scattering,and the scattering loss may be wavelength dependent. For example, thescattering loss may decrease as 1/(wavelength)³—so, the scattering lossdecreases with longer wavelengths. When there is a lesion in the dentine1703, more water can accumulate in the area, so there is also increasedwater absorption. For example, the dips near 1450 nm and 1900 nmcorrespond to water absorption, and the reflectance dips areparticularly pronounced in the dentine lesion 1703. One other benefit ofthe absorption, transmission or reflectance in the near infrared may bethat stains and non-calcified plaque are not visible in this wavelengthrange, enabling better discrimination of defects, cracks, anddemineralized areas.

Compared with the interference from skin 1000 in FIG. 10 or fingernails1400 in FIG. 14, the teeth appear to introduce much less interferencefor non-invasive monitoring of blood constituents. The few features inFIG. 16B or 17 may be calibrated out of the measurement. Also, using anintact tooth 1701 may further minimize any interfering signals.Furthermore, since the tooth comprises relatively hard tissue, higherpower from the light sources in the near infrared may be used withoutdamaging the tissue, such as with skin.

Human Interface for Measurement System

A number of different types of measurements may be used to sample theblood in the dental pulp. The basic feature of the measurements shouldbe that the optical properties are measured as a function of wavelengthat a plurality of wavelengths. As further described below, the lightsource may output a plurality of wavelengths, or a continuous spectrumover a range of wavelengths. In a preferred embodiment, the light sourcemay cover some or all of the wavelength range between approximately 1400nm and 2500 nm. The signal may be received at a receiver, which may alsocomprise a spectrometer or filters to discriminate between differentwavelengths. The signal may also be received at a camera, which may alsocomprise filters or a spectrometer. In an alternate embodiment, thespectral discrimination using filters or a spectrometer may be placedafter the light source rather than at the receiver. The receiver usuallycomprises one or more detectors (optical-to-electrical conversionelement) and electrical circuitry. The receiver may also be coupled toanalog to digital converters, particularly if the signal is to be fed toa digital device.

Referring to FIG. 15, one or more light sources 1511 may be used forillumination. In one embodiment, a transmission measurement may beperformed by directing the light source output 1511 to the region nearthe interface between the gum 1506 and dentine 1504. In one embodiment,the light may be directed using a light guide or a fiber optic. Thelight may then propagate through the dental pulp 1505 to the other side,where the light may be incident on one or more detectors or anotherlight guide to transport the signal to a spectrometer, receiver orcamera 1512. In another embodiment, the light source may be directed toone or more locations near the interface between the gum 1506 anddentine 1504 (in one example, could be from the two sides of the tooth).The transmitted light may then be detected in the occlusal surface abovethe tooth using a spectrometer, receiver, or camera 1512. In yet anotherembodiment, a reflectance measurement may be conducted by directing thelight source output 1511 to, for example, the occlusal surface of thetooth, and then detecting the reflectance at a spectrometer, receiver orcamera 1513. Although a few embodiments for measuring the bloodconstituents through a tooth are described, other embodiments andtechniques may also be used and are intended to be covered by thisdisclosure.

The human interface for the non-invasive measurement of bloodconstituents may be of various forms. In one embodiment, a “clamp”design 1800 may be used cap over one or more teeth, as illustrated inFIG. 18A. The clamp design may be different for different types ofteeth, or it may be flexible enough to fit over different types ofteeth. For example, different types of teeth include the molars (towardthe back of the mouth), the premolars, the canine, and the incisors(toward the front of the mouth). One embodiment of the clamp-type designis illustrated in FIG. 18A for a molar tooth 1808. The C-clamp 1801 maybe made of a plastic or rubber material, and it may comprise a lightsource input 1802 and a detector output 1803 on the front or back of thetooth.

The light source input 1802 may comprise a light source directly, or itmay have light guided to it from an external light source. Also, thelight source input 1802 may comprise a lens system to collimate or focusthe light across the tooth. The detector output 1803 may comprise adetector directly, or it may have a light guide to transport the signalto an external detector element. The light source input 1802 may becoupled electrically or optically through 1804 to a light input 1806.For example, if the light source is external in 1806, then the couplingelement 1804 may be a light guide, such as a fiber optic. Alternately,if the light source is contained in 1802, then the coupling element 1804may be electrical wires connecting to a power supply in 1806. Similarly,the detector output 1803 may be coupled to a detector output unit 1807with a coupling element 1805, which may be one or more electrical wiresor a light guide, such as a fiber optic. This is just one example of aclamp over one or more teeth, but other embodiments may also be used andare intended to be covered by this disclosure.

In yet another embodiment, one or more light source ports and sensorports may be used in a mouth-guard type design. For example, oneembodiment of a dental mouth guard 1850 is illustrated in FIG. 18B. Thestructure of the mouth guard 1851 may be similar to mouth guards used insports (e.g., when playing football or boxing) or in dental trays usedfor applying fluoride treatment, and the mouth guard may be made fromplastic or rubber materials, for example. As an example, the mouth guardmay have one or more light source input ports 1852, 1853 and one or moredetector output ports 1854, 1855. Although six input and output portsare illustrated, any number of ports may be used.

Similar to the clamp design describe above, the light source inputs1852, 1853 may comprise one or more light sources directly, or they mayhave light guided to them from an external light source. Also, the lightsource inputs 1852, 1853 may comprise lens systems to collimate or focusthe light across the teeth. The detector outputs 1854, 1855 may compriseone or more detectors directly, or they may have one or more lightguides to transport the signals to an external detector element. Thelight source inputs 1852, 1853 may be coupled electrically or opticallythrough 1856 to a light input 1857. For example, if the light source isexternal in 1857, then the one or more coupling elements 1856 may be oneor more light guides, such as a fiber optic. Alternately, if the lightsources are contained in 1852, 1853, then the coupling element 1856 maybe one or more electrical wires connecting to a power supply in 1857.Similarly, the detector outputs 1854, 1855 may be coupled to a detectoroutput unit 1859 with one or more coupling elements 1858, which may beone or more electrical wires or one or more light guides, such as afiber optic. This is just one example of a mouth guard design covering aplurality of teeth, but other embodiments may also be used and areintended to be covered by this disclosure. For instance, the position ofthe light source inputs and detector output ports could be exchanged, orsome mixture of locations of light source inputs and detector outputports could be used.

Other elements may be added to the human interface designs of FIG. 18and are also intended to be covered by this disclosure. For instance, inone embodiment it may be desirable to have replaceable inserts that maybe disposable. Particularly in a doctor's office or hospital setting,the same instrument may be used with a plurality of patients. Ratherthan disinfecting the human interface after each use, it may bepreferable to have disposable inserts that can be thrown away after eachuse. In one embodiment, a thin plastic coating material may enclose theclamp design of FIG. 18A or mouth guard design of FIG. 18B. The coatingmaterial may be inserted before each use, and then after the measurementis exercised the coating material may be peeled off and replaced. Such adesign may save the physician or user considerable time, while at thesame time provide the business venture with a recurring cost revenuesource. Any coating material or other disposable device may beconstructed of a material having suitable optical properties that may beconsidered during processing of the signals used to detect any anomaliesin the teeth.

Light Sources for Near Infrared

There are a number of light sources that may be used in the nearinfrared. To be more specific, the discussion below will consider lightsources operating in the so-called short wave infrared (SWIR), which maycover the wavelength range of approximately 1400 nm to 2500 nm. Otherwavelength ranges may also be used for the applications described inthis disclosure, so the discussion below is merely provided forexemplary types of light sources. The SWIR wavelength range may bevaluable for a number of reasons. First, the SWIR corresponds to atransmission window through water and the atmosphere. For example, 302in FIG. 3A and 1602 in FIG. 16A illustrate the water transmissionwindows. Also, through the atmosphere, wavelengths in the SWIR havesimilar transmission windows due to water vapor in the atmosphere.Second, the so-called “eye-safe” wavelengths are wavelengths longer thanapproximately 1400 nm. Third, the SWIR covers the wavelength range fornonlinear combinations of stretching and bending modes as well as thefirst overtone of C—H stretching modes. Thus, for example, glucose andketones among other substances may have unique signatures in the SWIR.Moreover, many solids have distinct spectral signatures in the SWIR, soparticular solids may be identified using stand-off detection or remotesensing. For instance, many explosives have unique signatures in theSWIR.

Different light sources may be selected for the SWIR based on the needsof the application. Some of the features for selecting a particularlight source include power or intensity, wavelength range or bandwidth,spatial or temporal coherence, spatial beam quality for focusing ortransmission over long distance, and pulse width or pulse repetitionrate. Depending on the application, lamps, light emitting diodes (LEDs),laser diodes (LD's), tunable LD's, super-luminescent laser diodes(SLDs), fiber lasers or super-continuum sources (SC) may beadvantageously used. Also, different fibers may be used for transportingthe light, such as fused silica fibers, plastic fibers, mid-infraredfibers (e.g., tellurite, chalcogenides, fluorides, ZBLAN, etc), or ahybrid of these fibers.

Lamps may be used if low power or intensity of light is required in theSWIR, and if an incoherent beam is suitable. In one embodiment, in theSWIR an incandescent lamp that can be used is based on tungsten andhalogen, which have an emission wavelength between approximately 500 nmto 2500 nm. For low intensity applications, it may also be possible touse thermal sources, where the SWIR radiation is based on the black bodyradiation from the hot object. Although the thermal and lamp basedsources are broadband and have low intensity fluctuations, it may bedifficult to achieve a high signal-to-noise ratio in a non-invasiveblood constituent measurement due to the low power levels. Also, thelamp based sources tend to be energy inefficient.

In another embodiment, LED's can be used that have a higher power levelin the SWIR wavelength range. LED's also produce an incoherent beam, butthe power level can be higher than a lamp and with higher energyefficiency. Also, the LED output may more easily be modulated, and theLED provides the option of continuous wave or pulsed mode of operation.LED's are solid state components that emit a wavelength band that is ofmoderate width, typically between about 20 nm to 40 nm. There are alsoso-called super-luminescent LEDs that may even emit over a much widerwavelength range. In another embodiment, a wide band light source may beconstructed by combining different LEDs that emit in differentwavelength bands, some of which could preferably overlap in spectrum.One advantage of LEDs as well as other solid state components is thecompact size that they may be packaged into.

In yet another embodiment, various types of laser diodes may be used inthe SWIR wavelength range. Just as LEDs may be higher in power butnarrower in wavelength emission than lamps and thermal sources, the LDsmay be yet higher in power but yet narrower in wavelength emission thanLEDs. Different kinds of LDs may be used, including Fabry-Perot LDs,distributed feedback (DFB) LDs, distributed Bragg reflector (DBR) LDs.Since the LDs have relatively narrow wavelength range (typically under10 nm), in one embodiment a plurality of LDs may be used that are atdifferent wavelengths in the SWIR. For example, in a preferredembodiment for non-invasive glucose monitoring, it may be advantageousto use LDs having emission spectra near some or all of the glucosespectral peaks (e.g., near 1587 nm, 1750 nm, 2120 nm, 2270 nm, and 2320nm). The various LDs may be spatially multiplexed, polarizationmultiplexed, wavelength multiplexed, or a combination of thesemultiplexing methods. Also, the LDs may be fiber pig-tailed or have oneor more lenses on the output to collimate or focus the light. Anotheradvantage of LDs is that they may be packaged compactly and may have aspatially coherent beam output. Moreover, tunable LDs that can tune overa range of wavelengths are also available. The tuning may be done byvarying the temperature, or electrical current may be used in particularstructures, such as distributed Bragg reflector LDs. In anotherembodiment, external cavity LDs may be used that have a tuning element,such as a fiber grating or a bulk grating, in the external cavity.

In another embodiment, super-luminescent laser diodes may provide higherpower as well as broad bandwidth. An SLD is typically an edge emittingsemiconductor light source based on super-luminescence (e.g., this couldbe amplified spontaneous emission). SLDs combine the higher power andbrightness of LDs with the low coherence of conventional LEDs, and theemission band for SLD's may be 5 to 100 nm wide, preferably in the 60 to100 nm range. Although currently SLDs are commercially available in thewavelength range of approximately 400 nm to 1700 nm, SLDs could and mayin the future be made to cover a broader region of the SWIR.

In yet another embodiment, high power LDs for either direct excitationor to pump fiber lasers and SC light sources may be constructed usingone or more laser diode bar stacks. As an example, FIG. 19 shows anexample of the block diagram 1900 or building blocks for constructingthe high power LDs. In this embodiment, one or more diode bar stacks1901 may be used, where the diode bar stack may be an array of severalsingle emitter LDs. Since the fast axis (e.g., vertical direction) maybe nearly diffraction limited while the slow-axis (e.g., horizontalaxis) may be far from diffraction limited, different collimators 1902may be used for the two axes.

Then, the brightness may be increased by spatially combining the beamsfrom multiple stacks 1903. The combiner may include spatialinterleaving, it may include wavelength multiplexing, or it may involvea combination of the two. Different spatial interleaving schemes may beused, such as using an array of prisms or mirrors with spacers to bendone array of beams into the beam path of the other. In anotherembodiment, segmented mirrors with alternate high-reflection andanti-reflection coatings may be used. Moreover, the brightness may beincreased by polarization beam combining 1904 the two orthogonalpolarizations, such as by using a polarization beam splitter. In oneembodiment, the output may then be focused or coupled into a largediameter core fiber. As an example, typical dimensions for the largediameter core fiber range from approximately 100 microns in diameter to400 microns or more. Alternatively or in addition, a custom beam shapingmodule 1905 may be used, depending on the particular application. Forexample, the output of the high power LD may be used directly 1906, orit may be fiber coupled 1907 to combine, integrate, or transport thehigh power LD energy. These high power LDs may grow in importancebecause the LD powers can rapidly scale up. For example, instead of thepower being limited by the power available from a single emitter, thepower may increase in multiples depending on the number of diodesmultiplexed and the size of the large diameter fiber. Although FIG. 19is shown as one embodiment, some or all of the elements may be used in ahigh power LD, or additional elements may also be used.

SWIR Super-Continuum Lasers

Each of the light sources described above have particular strengths, butthey also may have limitations. For example, there is typically atrade-off between wavelength range and power output. Also, sources suchas lamps, thermal sources, and LEDs produce incoherent beams that may bedifficult to focus to a small area and may have difficulty propagatingfor long distances. An alternative source that may overcome some ofthese limitations is an SC light source. Some of the advantages of theSC source may include high power and intensity, wide bandwidth,spatially coherent beam that can propagate nearly transform limited overlong distances, and easy compatibility with fiber delivery.

Supercontinuum lasers may combine the broadband attributes of lamps withthe spatial coherence and high brightness of lasers. By exploiting amodulational instability initiated supercontinuum (SC) mechanism, anall-fiber-integrated SC laser with no moving parts may be built usingcommercial-off-the-shelf (COTS) components. Moreover, the fiber laserarchitecture may be a platform where SC in the visible,near-infrared/SWIR, or mid-IR can be generated by appropriate selectionof the amplifier technology and the SC generation fiber. But until now,SC lasers were used primarily in laboratory settings since typicallylarge, table-top, mode-locked lasers were used to pump nonlinear mediasuch as optical fibers to generate SC light. However, those large pumplasers may now be replaced with diode lasers and fiber amplifiers thatgained maturity in the telecommunications industry.

In one embodiment, an all-fiber-integrated, high-powered SC light source2000 may be elegant for its simplicity (FIG. 20). The light may be firstgenerated from a seed laser diode 2001. For example, the seed LD 2001may be a distributed feedback laser diode with a wavelength near 1542 or1550 nm, with approximately 0.5-2.0 ns pulsed output, and with a pulserepetition rate between a kilohertz to about 100 MHz or more. The outputfrom the seed laser diode may then be amplified in a multiple-stagefiber amplifier 2002 comprising one or more gain fiber segments. In oneembodiment, the first stage pre-amplifier 2003 may be designed foroptimal noise performance. For example, the pre-amplifier 2003 may be astandard erbium-doped fiber amplifier or an erbium/ytterbium dopedcladding pumped fiber amplifier. Between amplifier stages 2003 and 2006,it may be advantageous to use band-pass filters 2004 to block amplifiedspontaneous emission and isolators 2005 to prevent spurious reflections.Then, the power amplifier stage 2006 may use a cladding-pumped fiberamplifier that may be optimized to minimize nonlinear distortion. Thepower amplifier fiber 2006 may also be an erbium-doped fiber amplifier,if only low or moderate power levels are to be generated.

The SC generation 2007 may occur in the relatively short lengths offiber that follow the pump laser. In one exemplary embodiment, the SCfiber length may range from a few millimeters to 100 m or more. In oneembodiment, the SC generation may occur in a first fiber 2008 where themodulational-instability initiated pulse break-up primarily occurs,followed by a second fiber 2009 where the SC generation and spectralbroadening primarily occurs.

In one embodiment, one or two meters of standard single-mode fiber (SMF)after the power amplifier stage may be followed by several meters of SCgeneration fiber. For this example, in the SMF the peak power may beseveral kilowatts and the pump light may fall in the anomalousgroup-velocity dispersion regime—often called the soliton regime. Forhigh peak powers in the dispersion regime, the nanosecond pulses may beunstable due to a phenomenon known as modulational instability, which isbasically parametric amplification in which the fiber nonlinearity helpsto phase match the pulses. As a consequence, the nanosecond pump pulsesmay be broken into many shorter pulses as the modulational instabilitytries to form soliton pulses from the quasi-continuous-wave background.Although the laser diode and amplification process starts withapproximately nanosecond-long pulses, modulational instability in theshort length of SMF fiber may form approximately 0.5 ps toseveral-picosecond-long pulses with high intensity. Thus, the few metersof SMF fiber may result in an output similar to that produced bymode-locked lasers, except in a much simpler and cost-effective manner.

The short pulses created through modulational instability may then becoupled into a nonlinear fiber for SC generation. The nonlinearmechanisms leading to broadband SC may include four-wave mixing orself-phase modulation along with the optical Raman effect. Since theRaman effect is self-phase-matched and shifts light to longerwavelengths by emission of optical photons, the SC may spread to longerwavelengths very efficiently. The short-wavelength edge may arise fromfour-wave mixing, and often times the short wavelength edge may belimited by increasing group-velocity dispersion in the fiber. In manyinstances, if the particular fiber used has sufficient peak power and SCfiber length, the SC generation process may fill the long-wavelengthedge up to the transmission window.

Mature fiber amplifiers for the power amplifier stage 2006 includeytterbium-doped fibers (near 1060 nm), erbium-doped fibers (near 1550nm), erbium/ytterbium-doped fibers (near 1550 nm), or thulium-dopedfibers (near 2000 nm). In various embodiments, candidates for SC fiber2009 include fused silica fibers (for generating SC between 0.8-2.7 μm),mid-IR fibers such as fluorides, chalcogenides, or tellurites (forgenerating SC out to 4.5 μm or longer), photonic crystal fibers (forgenerating SC between 0.4 and 1.7 μm), or combinations of these fibers.Therefore, by selecting the appropriate fiber-amplifier doping for 2006and nonlinear fiber 2009, SC may be generated in the visible,near-IR/SWIR, or mid-IR wavelength region.

The configuration 2000 of FIG. 20 is just one particular example, andother configurations can be used and are intended to be covered by thisdisclosure. For example, further gain stages may be used, and differenttypes of lossy elements or fiber taps may be used between the amplifierstages. In another embodiment, the SC generation may occur partially inthe amplifier fiber and in the pig-tails from the pump combiner or otherelements. In yet another embodiment, polarization maintaining fibers maybe used, and a polarizer may also be used to enhance the polarizationcontrast between amplifier stages. Also, not discussed in detail aremany accessories that may accompany this set-up, such as driverelectronics, pump laser diodes, safety shut-offs, and thermal managementand packaging.

One example of an SC laser that operates in the SWIR used in oneembodiment is illustrated in FIG. 21. This SWIR SC source 2100 producesan output of up to approximately 5 W over a spectral range of about 1.5to 2.4 microns, and this particular laser is made out of polarizationmaintaining components. The seed laser 2101 is a distributed feedback(DFB) laser operating near 1542 nm producing approximately 0.5nanosecond (ns) pulses at an about 8 MHz repetition rate. Thepre-amplifier 2102 is forward pumped and uses about 2 m length oferbium/ytterbium cladding pumped fiber 2103 (often also called dual-corefiber) with an inner core diameter of 12 microns and outer core diameterof 130 microns. The pre-amplifier gain fiber 2103 is pumped using a 10 W940 nm laser diode 2105 that is coupled in using a fiber combiner 2104.

In this particular 5 W unit, the mid-stage between amplifier stages 2102and 2106 comprises an isolator 2107, a band-pass filter 2108, apolarizer 2109 and a fiber tap 2110. The power amplifier 2106 uses a 4 mlength of the 12/130 micron erbium/ytterbium doped fiber 2111 that iscounter-propagating pumped using one or more 30 W 940 nm laser diodes2112 coupled in through a combiner 2113. An approximately 1-2 meterlength of the combiner pig-tail helps to initiate the SC process, andthen a length of PM-1550 fiber 2115 (polarization maintaining,single-mode, fused silica fiber optimized for 1550 nm) is spliced 2114to the combiner output.

If an output fiber of about 10 m in length is used, then the resultingoutput spectrum 2200 is shown in FIG. 22. The details of the outputspectrum 2200 depend on the peak power into the fiber, the fiber length,and properties of the fiber such as length and core size, as well as thezero dispersion wavelength and the dispersion properties. For example,if a shorter length of fiber is used, then the spectrum actually reachesto longer wavelengths (e.g., a 2 m length of SC fiber broadens thespectrum to ˜2500 nm). Also, if extra-dry fibers are used with less O—Hcontent, then the wavelength edge may also reach to a longer wavelength.To generate more spectrum toward the shorter wavelengths, the pumpwavelength (in this case ˜1542 nm) should be close to the zerodispersion wavelength in the fiber. For example, by using a dispersionshifted fiber or so-called non-zero dispersion shifted fiber, the shortwavelength edge may shift to shorter wavelengths.

Although one particular example of a 5 W SWIR-SC has been described,different components, different fibers, and different configurations mayalso be used consistent with this disclosure. For instance, anotherembodiment of the similar configuration 2100 in FIG. 21 may be used togenerate high powered SC between approximately 1060 and 1800 nm. Forthis embodiment, the seed laser 2101 may be a 1064 nm distributedfeedback (DFB) laser diode, the pre-amplifier gain fiber 2103 may be aytterbium-doped fiber amplifier with 10/125 microns dimensions, and thepump laser 2105 may be a 10 W 915 nm laser diode. In the mid-stage, amode field adapter may be included in addition to the isolator 2107,band pass filter 2108, polarizer 2109 and tap 2110. The gain fiber 2111in the power amplifier may be a 20 m length of ytterbium-doped fiberwith 25/400 microns dimension for example. The pump 2112 for the poweramplifier may be up to six pump diodes providing 30 W each near 915 nm,for example. For this much pump power, the output power in the SC may beas high as 50 W or more.

In another embodiment, it may be desirous to generate high power SWIR SCover 1.4-1.8 microns and separately 2-2.5 microns (the window between1.8 and 2 microns may be less important due to the strong water andatmospheric absorption). For example, the top SC source of FIG. 23 canlead to bandwidths ranging from about 1400 nm to 1800 nm or broader,while the lower SC source of FIG. 23 can lead to bandwidths ranging fromabout 1900 nm to 2500 nm or broader. Since these wavelength ranges areshorter than about 2500 nm, the SC fiber can be based on fused silicafiber. Exemplary SC fibers include standard single-mode fiber SMF,high-nonlinearity fiber, high-NA fiber, dispersion shifted fiber,dispersion compensating fiber, and photonic crystal fibers.Non-fused-silica fibers can also be used for SC generation, includingchalcogenides, fluorides, ZBLAN, tellurites, and germanium oxide fibers.

In one embodiment, the top of FIG. 23 illustrates a block diagram for anSC source 2300 capable of generating light between approximately 1400and 1800 nm or broader. As an example, a pump fiber laser similar toFIG. 21 can be used as the input to a SC fiber 2309. The seed laserdiode 2301 can comprise a DFB laser that generates, for example, severalmilliwatts of power around 1542 or 1553 nm. The fiber pre-amplifier 2302can comprise an erbium-doped fiber amplifier or an erbium/ytterbiumdoped double clad fiber. In this example a mid-stage amplifier 2303 canbe used, which can comprise an erbium/ytterbium doped double-clad fiber.A bandpass filter 2305 and isolator 2306 may be used between thepre-amplifier 2302 and mid-stage amplifier 2303. The power amplifierstage 2304 can comprise a larger core size erbium/ytterbium dopeddouble-clad fiber, and another bandpass filter 2307 and isolator 2308can be used before the power amplifier 2304. The output of the poweramplifier can be coupled to the SC fiber 2309 to generate the SC output2310. This is just one exemplary configuration for an SC source, andother configurations or elements may be used consistent with thisdisclosure.

In yet another embodiment, the bottom of FIG. 23 illustrates a blockdiagram for an SC source 2350 capable of generating light betweenapproximately 1900 and 2500 nm or broader. As an example, the seed laserdiode 2351 can comprise a DFB or DBR laser that generates, for example,several milliwatts of power around 1542 or 1553 nm. The fiberpre-amplifier 2352 can comprise an erbium-doped fiber amplifier or anerbium/ytterbium doped double-clad fiber. In this example a mid-stageamplifier 2353 can be used, which can comprise an erbium/ytterbium dopeddouble-clad fiber. A bandpass filter 2355 and isolator 2356 may be usedbetween the pre-amplifier 2352 and mid-stage amplifier 2353. The poweramplifier stage 2354 can comprise a thulium doped double-clad fiber, andanother isolator 2357 can be used before the power amplifier 2354. Notethat the output of the mid-stage amplifier 2353 can be approximatelynear 1550 nm, while the thulium-doped fiber amplifier 2354 can amplifywavelengths longer than approximately 1900 nm and out to about 2100 nm.Therefore, for this configuration wavelength shifting may be requiredbetween 2353 and 2354. In one embodiment, the wavelength shifting can beaccomplished using a length of standard single-mode fiber 2358, whichcan have a length between approximately 5 and 50 meters, for example.The output of the power amplifier 2354 can be coupled to the SC fiber2359 to generate the SC output 2360. This is just one exemplaryconfiguration for an SC source, and other configurations or elements canbe used consistent with this disclosure. For example, the variousamplifier stages can comprise different amplifier types, such as erbiumdoped fibers, ytterbium doped fibers, erbium/ytterbium co-doped fibersand thulium doped fibers. One advantage of the SC lasers illustrated inFIGS. 20-23 are that they may use all-fiber components, so that the SClaser can be all-fiber, monolithically integrated with no moving parts.The all-integrated configuration can consequently be robust andreliable.

FIGS. 20-23 are examples of SC light sources that may be advantageouslyused for SWIR light generation in various medical diagnostic andtherapeutic applications. However, many other versions of the SC lightsources may also be made that are intended to also be covered by thisdisclosure. For example, the SC generation fiber could be pumped by amode-locked laser, a gain-switched semiconductor laser, an opticallypumped semiconductor laser, a solid state laser, other fiber lasers, ora combination of these types of lasers. Also, rather than using a fiberfor SC generation, either a liquid or a gas cell might be used as thenonlinear medium in which the spectrum is to be broadened.

Even within the all-fiber versions illustrated such as in FIG. 21,different configurations could be used consistent with the disclosure.In an alternate embodiment, it may be desirous to have a lower costversion of the SWIR SC laser of FIG. 21. One way to lower the cost couldbe to use a single stage of optical amplification, rather than twostages, which may be feasible if lower output power is required or thegain fiber is optimized. For example, the pre-amplifier stage 2102 mightbe removed, along with at least some of the mid-stage elements. In yetanother embodiment, the gain fiber could be double passed to emulate atwo stage amplifier. In this example, the pre-amplifier stage 2102 mightbe removed, and perhaps also some of the mid-stage elements. A mirror orfiber grating reflector could be placed after the power amplifier stage2106 that may preferentially reflect light near the wavelength of theseed laser 2101. If the mirror or fiber grating reflector can transmitthe pump light near 940 nm, then this could also be used instead of thepump combiner 2113 to bring in the pump light 2112. The SC fiber 2115could be placed between the seed laser 2101 and the power amplifierstage 2106 (SC is only generated after the second pass through theamplifier, since the power level may be sufficiently high at that time).In addition, an output coupler may be placed between the seed laserdiode 2101 and the SC fiber, which now may be in front of the poweramplifier 2106. In a particular embodiment, the output coupler could bea power coupler or divider, a dichroic coupler (e.g., passing seed laserwavelength but outputting the SC wavelengths), or a wavelength divisionmultiplexer coupler. This is just one further example, but a myriad ofother combinations of components and architectures could also be usedfor SC light sources to generate SWIR light that are intended to becovered by this disclosure.

Wireless Link to the Cloud

The non-invasive blood constituent or analytes measurement device mayalso benefit from communicating the data output to the “cloud” (e.g.,data servers and processors in the web remotely connected) via wiredand/or wireless communication strategies. The non-invasive devices maybe part of a series of biosensors applied to the patient, andcollectively these devices form what might be called a body area networkor a personal area network. The biosensors and non-invasive devices maycommunicate to a smart phone, tablet, personal data assistant, computer,and/or other microprocessor-based device, which may in turn wirelesslyor over wire and/or fiber optically transmit some or all of the signalor processed data to the internet or cloud. The cloud or internet may inturn send the data to doctors or health care providers as well as thepatients themselves. Thus, it may be possible to have a panoramic,high-definition, relatively comprehensive view of a patient that doctorscan use to assess and manage disease, and that patients can use to helpmaintain their health and direct their own care.

In a particular embodiment 2400, the physiological measurement device ornon-invasive blood constituent measurement device 2401 may comprise atransmitter 2403 to communicate over a first communication link 2404 inthe body area network or personal area network to a receiver in a smartphone, tablet cell phone, PDA, or computer 2405. For the measurementdevice 2401, it may also be advantageous to have a processor 2402 toprocess some of the physiological data, since with processing the amountof data to transmit may be less (hence, more energy efficient). Thefirst communication link 2404 may operate through the use of one of manywireless technologies such as Bluetooth, Zigbee, WiFi, IrDA (infrareddata association), wireless USB, or Z-wave, to name a few.Alternatively, the communication link 2404 may occur in the wirelessmedical band between 2360 and 2390 MHz, which the FCC allocated formedical body area network devices, or in other designated medical deviceor WMTS bands. These are examples of devices that can be used in thebody area network and surroundings, but other devices could also be usedand are included in the scope of this disclosure.

The personal device 2405 may store, process, display, and transmit someof the data from the measurement device 2401. The device 2405 maycomprise a receiver, transmitter, display, voice control and speakers,and one or more control buttons or knobs and a touch screen. Examples ofthe device 2405 include smart phones such as the Apple iPhones® orphones operating on the Android or Microsoft systems. In one embodiment,the device 2405 may have an application, software program, or firmwareto receive and process the data from the measurement device 2401. Thedevice 2405 may then transmit some or all of the data or the processeddata over a second communication link 2406 to the internet or “cloud”2407. The second communication link 2406 may advantageously comprise atleast one segment of a wireless transmission link, which may operateusing WiFi or the cellular network. The second communication link 2406may additionally comprise lengths of fiber optic and/or communicationover copper wires or cables.

The internet or cloud 2407 may add value to the measurement device 2401by providing services that augment the physiological data collected. Ina particular embodiment, some of the functions performed by the cloudinclude: (a) receive at least a fraction of the data from the device2405; (b) buffer or store the data received; (c) process the data usingsoftware stored on the cloud; (d) store the resulting processed data;and (e) transmit some or all of the data either upon request or based onan alarm. As an example, the data or processed data may be transmitted2408 back to the originator (e.g., patient or user), it may betransmitted 2409 to a health care provider or doctor, or it may betransmitted 2410 to other designated recipients.

The cloud 2407 may provide a number of value-add services. For example,the cloud application may store and process the physiological data forfuture reference or during a visit with the healthcare provider. If apatient has some sort of medical mishap or emergency, the physician canobtain the history of the physiological parameters over a specifiedperiod of time. In another embodiment, if the physiological parametersfall out of acceptable range, alarms may be delivered to the user 2408,the healthcare provider 2409, or other designated recipients 2410. Theseare just some of the features that may be offered, but many others maybe possible and are intended to be covered by this disclosure. As anexample, the device 2405 may also have a GPS sensor, so the cloud 2407may be able to provide time, data and position along with thephysiological parameters. Thus, if there is a medical emergency, thecloud 2407 could provide the location of the patient to the healthcareprovider 2409 or other designated recipients 2410. Moreover, thedigitized data in the cloud 2407 may help to move toward what is oftencalled “personalized medicine.” Based on the physiological parameterdata history, medication or medical therapies may be prescribed that arecustomized to the particular patient.

Beyond the above benefits, the cloud application 2407 and application onthe device 2405 may also have financial value for companies developingmeasurement devices 2401 such as a non-invasive blood constituentmonitor. In the case of glucose monitors, the companies make themajority of their revenue on the measurement strips. However, with anon-invasive monitor, there is no need for strips, so there is less ofan opportunity for recurring costs (e.g., the razor/razor blade modeldoes not work for non-invasive devices). On the other hand, people maybe willing to pay a periodic fee for the value-add services provided onthe cloud 2407. Diabetic patients, for example, would probably bewilling to pay a periodic fee for monitoring their glucose levels,storing the history of the glucose levels, and having alarm warningswhen the glucose level falls out of range. Similarly, patients takingketone bodies supplement for treatment of disorders characterized byimpaired glucose metabolism (e.g., Alzheimer's, Parkinson's,Huntington's or ALS) may need to monitor their ketone bodies level.These patients would also probably be willing to pay a periodic fee forthe value-add services provided on the cloud 2407. Thus, by leveragingthe advances in wireless connectivity and the widespread use of handhelddevices such as smart phones that can wirelessly connect to the cloud,businesses can build a recurring cost business model even usingnon-invasive measurement devices.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for non-invasive monitoring of glucose,ketones, HbA1c and other blood constituents. However, many other medicalprocedures can use the near-infrared or SWIR light consistent with thisdisclosure and are intended to be covered by the disclosure.

Section 2: Short-Wave Infrared Super-Continuum Lasers for EarlyDetection of Dental Caries

Near-infrared (NIR) and SWIR light may be preferred for caries detectioncompared to visible light imaging because the NIR/SWIR wavelengthsgenerally have lower absorption by stains and deeper penetration intoteeth. Hence, NIR/SWIR light may provide a caries detection method thatcan be non-invasive, non-contact and relatively stain insensitive.Broadband light may provide further advantages because carious regionsmay demonstrate spectral signatures from water absorption and thewavelength dependence of porosity in the scattering of light.

In general, the near-infrared region of the electromagnetic spectrumcovers between approximately 0.7 microns (700 nm) to about 2.5 microns(2500 nm). However, it may also be advantageous to use just theshort-wave infrared between approximately 1.4 microns (1400 nm) andabout 2.5 microns (2500 nm). One reason for preferring the SWIR over theentire NIR may be to operate in the so-called “eye safe” window, whichcorresponds to wavelengths longer than about 1400 nm. Therefore, for theremainder of the disclosure the SWIR will be used for illustrativepurposes. However, it should be clear that the discussion that followscould also apply to using the NIR wavelength range, or other wavelengthbands.

In particular, wavelengths in the eye safe window may not transmit downto the retina of the eye, and therefore, these wavelengths may be lesslikely to create permanent eye damage from inadvertent exposure. Thenear-infrared wavelengths have the potential to be dangerous, becausethe eye cannot see the wavelengths (as it can in the visible), yet theycan penetrate and cause damage to the eye. Even if a practitioner is notlooking directly at the laser beam, the practitioner's eyes may receivestray light from a reflection or scattering from some surface. Hence, itcan always be a good practice to use eye protection when working aroundlasers. Since wavelengths longer than about 1400 nm are substantiallynot transmitted to the retina or substantially absorbed in the retina,this wavelength range is known as the eye safe window. For wavelengthslonger than 1400 nm, in general only the cornea of the eye may receiveor absorb the light radiation.

FIG. 25 illustrates the structure of an exemplary cross-section of atooth 2500. The tooth 2500 has a top layer called the crown 2501 andbelow that a root 2502 that reaches well into the gum 2506 and bone 2508of the mouth. The exterior of the crown 2501 is an enamel layer 2503,and below the enamel is a layer of dentine 2504 that sits atop a layerof cementum 2507. Below the dentine 2504 is a pulp region 2505, whichcomprises within it blood vessels 2509 and nerves 2510. If the light canpenetrate the enamel 2503 and dentine 2504, then the blood flow andblood constituents may be measured through the blood vessels in thedental pulp 2505. While the amount of blood flow in the capillaries ofthe dental pulp 2505 may be less than an artery or vein, the smallerblood flow could still be advantageous for detecting or measuring bloodconstituents as compared to detection through the skin if there is lessinterfering spectral features from the tooth.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. As used throughout this disclosure, the term “spectroscopy”means that a tissue or sample is inspected by comparing differentfeatures, such as wavelength (or frequency), spatial location,transmission, absorption, reflectivity, scattering, refractive index, oropacity. In one embodiment, “spectroscopy” may mean that the wavelengthof the light source is varied, and the transmission, absorption, orreflectivity of the tissue or sample is measured as a function ofwavelength. In another embodiment, “spectroscopy” may mean that thewavelength dependence of the transmission, absorption or reflectivity iscompared between different spatial locations on a tissue or sample. Asan illustration, the “spectroscopy” may be performed by varying thewavelength of the light source, or by using a broadband light source andanalyzing the signal using a spectrometer, wavemeter, or opticalspectrum analyzer.

As used throughout this disclosure, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium, for example.In another embodiment, the mid-infrared fiber may comprise one or acombination of fluoride fiber, ZBLAN fiber, chalcogenide fiber,tellurite fiber, or germanium doped fiber. In yet another embodiment,the single mode fiber may include standard single-mode fiber, dispersionshifted fiber, non-zero dispersion shifted fiber, high-nonlinearityfiber, and small core size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium, and/orthulium. In one embodiment, the “pump laser” may be a fiber laser, asolid state laser, a laser involving a nonlinear crystal, an opticalparametric oscillator, a semiconductor laser, or a plurality ofsemiconductor lasers that may be multiplexed together. In anotherembodiment, the “pump laser” may be coupled to the gain medium by usinga fiber coupler, a dichroic mirror, a multiplexer, a wavelength divisionmultiplexer, a grating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth or at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, the Ramaneffect, modulational instability, and self-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

Transmission or Reflection Through Teeth

The transmission, absorption and reflection from teeth has been studiedin the near infrared, and, although there are some features, the enameland dentine appear to be fairly transparent in the near infrared(particularly SWIR wavelengths between about 1400 and 2500 nm). Forexample, the absorption or extinction ratio for light transmission hasbeen studied. FIG. 26A illustrates the attenuation coefficient 2600 fordental enamel 2601 (filled circles) and the absorption coefficient ofwater 2602 (open circles) versus wavelength. Near-infrared light maypenetrate much further without scattering through all the tooth enamel,due to the reduced scattering coefficient in normal enamel. Scatteringin enamel may be fairly strong in the visible, but decreases asapproximately 1/(wavelength)3 [i.e., inverse of the cube of thewavelength] with increasing wavelength to a value of only 2-3 cm−1 at1310 nm and 1550 nm in the near infrared. Therefore, enamel may bevirtually transparent in the near infrared with optical attenuation 1-2orders of magnitude less than in the visible range.

As another example, FIG. 26B illustrates the absorption spectrum 2650 ofintact enamel 2651 (dashed line) and dentine 2652 (solid line) in thewavelength range of approximately 1.2 to 2.4 microns. In the nearinfrared there are two absorption bands in the areas of about 1.5 and 2microns. The band with a peak around 1.57 microns may be attributed tothe overtone of valent vibration of water present in both enamel anddentine. In this band, the absorption is greater for dentine than forenamel, which may be related to the large water content in this tissue.In the region of 2 microns, dentine may have two absorption bands, andenamel one. The band with a maximum near 2.1 microns may belong to theovertone of vibration of PO hydroxyapatite groups, which is the mainsubstance of both enamel and dentine. Moreover, the band with a peaknear 1.96 microns in dentine may correspond to water absorption (dentinemay contain substantially higher water than enamel).

In addition to the absorption coefficient, the reflectance from intactteeth and teeth with dental caries (e.g., cavities) has been studied. Inone embodiment, FIG. 27 shows the near infrared spectral reflectance2700 over the wavelength range of approximately 800 nm to 2500 nm froman occlusal (e.g., top) tooth surface 2704. The curve with blackdiamonds 2701 corresponds to the reflectance from a sound, intact toothsection. The curve with asterisks (*) 2702 corresponds to a toothsection with an enamel lesion. The curve with circles 2703 correspondsto a tooth section with a dentine lesion. Thus, when there is a lesion,more scattering occurs and there may be an increase in the reflectedlight.

For wavelengths shorter than approximately 1400 nm, the shapes of thespectra remain similar, but the amplitude of the reflection changes withlesions. Between approximately 1400 nm and 2500 nm, an intact tooth 2701has low reflectance (e.g., high transmission), and the reflectanceappears to be more or less independent of wavelength. On the other hand,in the presence of lesions 2702 and 2703, there is increased scattering,and the scattering loss may be wavelength dependent. For example, thescattering loss may decrease as the inverse of some power of wavelength,such as 1/(wavelength)3—so, the scattering loss decreases with longerwavelengths. When there is a lesion in the dentine 2703, more water canaccumulate in the area, so there is also increased water absorption. Forexample, the dips near 1450 nm and 1900 nm may correspond to waterabsorption, and the reflectance dips are particularly pronounced in thedentine lesion 2703.

FIG. 27 may point to several novel techniques for early detection andquantification of carious regions. One method may be to use a relativelynarrow wavelength range (for example, from a laser diode orsuper-luminescent laser diode) in the wavelength window below 1400 nm.In one embodiment, wavelengths in the vicinity of 1310 nm may be used,which is a standard telecommunications wavelength where appropriatelight sources are available. Also, it may be advantageous to use asuper-luminescent laser diode rather than a laser diode, because thebroader bandwidth may avoid the production of laser speckle that canproduce interference patterns due to light's scattering after strikingirregular surfaces. As FIG. 27 shows, the amplitude of the reflectedlight (which may also be proportional to the inverse of thetransmission) may increase with dental caries. Hence, comparing thereflected light from a known intact region with a suspect region mayhelp identify carious regions. However, one difficulty with using arelatively narrow wavelength range and relying on amplitude changes maybe the calibration of the measurement. For example, the amplitude of thereflected light may depend on many factors, such as irregularities inthe dental surface, placement of the light source and detector, distanceof the measurement instrument from the tooth, etc.

In one embodiment, use of a plurality of wavelengths can help to bettercalibrate the dental caries measurement. For example, a plurality oflaser diodes or super-luminescent laser diodes may be used at differentcenter wavelengths. Alternately, a lamp or alternate broadband lightsource may be used followed by appropriate filters, which may be placedafter the light source or before the detectors. In one example,wavelengths near 1090 nm, 1440 nm and 1610 nm may be employed. Thereflection from the tooth 2705 appears to reach a local maximum near1090 nm in the representative embodiment illustrated. Also, thereflectance near 1440 nm 2706 is higher for dental caries, with adistinct dip particularly for dentine caries 2703. Near 1610 nm 2707,the reflection is also higher for carious regions. By using a pluralityof wavelengths, the values at different wavelengths may help quantify acaries score. In one embodiment, the degree of enamel lesions may beproportional to the ratio of the reflectance near 1610 nm divided by thereflectance near 1090 nm. Also, the degree of dentine lesion may beproportional to the difference between the reflectance near 1610 nm and1440 nm, with the difference then divided by the reflectance near 1090nm. Although one set of wavelengths has been described, otherwavelengths may also be used and are intended to be covered by thisdisclosure.

In yet another embodiment, it may be further advantageous to use all ofsome fraction of the SWIR between approximately 1400 and 2500 nm. Forexample, a SWIR super-continuum light source could be used, or a lampsource could be used. On the receiver side, a spectrometer and/ordispersive element could be used to discriminate the variouswavelengths. As FIG. 27 shows, an intact tooth 2701 has a relatively lowand featureless reflectance over the SWIR. On the other hand, with acarious region there is more scattering, so the reflectance 2702, 2703increases in amplitude. Since the scattering is inversely proportionalto wavelength or some power of wavelength, the carious regionreflectance 2702, 2703 also decreases with increasing wavelength.Moreover, the carious region may contain more water, so there are dipsin the reflectance near the water absorption lines 2706 and 2708. Thedegree of caries or caries score may be quantified by the shape of thespectrum over the SWIR, taking ratios of different parts of thespectrum, or some combination of this and other spectral processingmethods.

Although several methods of early caries detection using spectralreflectance have been described, other techniques could also be used andare intended to be covered by this disclosure. For example,transmittance may be used rather than reflectance, or a combination ofthe two could be used. Moreover, the transmittance, reflectance and/orabsorbance could also be combined with other techniques, such asquantitative light-induced fluorescence or fiber-optictrans-illumination. Also, the SWIR could be advantageous, but otherparts of the infrared, near-infrared or visible wavelengths may also beused consistent with this disclosure.

One other benefit of the absorption, transmission or reflectance in thenear infrared and SWIR may be that stains and non-calcified plaque arenot visible in this wavelength range, enabling better discrimination ofdefects, cracks, and demineralized areas. For example, dental calculus,accumulated plaque, and organic stains and debris may interferesignificantly with visual diagnosis and fluorescence-based cariesdetection schemes in occlusal surfaces. In the case of usingquantitative light-induced fluorescence, such confounding factorstypically may need to be removed by prophylaxis (abrasive cleaning)before reliable measurements can be taken. Surface staining at visiblewavelengths may further complicate the problem, and it may be difficultto determine whether pits and fissures are simply stained ordemineralized. On the other hand, staining and pigmentation generallyinterfere less with NIR or SWIR imaging. For example, NIR and SWIR lightmay not be absorbed by melanin and porphyrins produced by bacteria andthose found in food dyes that accumulate in dental plaque and areresponsible for the pigmentation.

Human Interface for Measurement System

A number of different types of measurements may be used to image fordental caries, particularly early detection of dental caries. A basicfeature of the measurements may be that the optical properties aremeasured as a function of wavelength at a plurality of wavelengths. Asfurther described below, the light source may output a plurality ofwavelengths, or a continuous spectrum over a range of wavelengths. Inone embodiment, the light source may cover some or all of the wavelengthrange between approximately 1400 nm and 2500 nm. The signal may bereceived at a receiver, which may also comprise a spectrometer orfilters to discriminate between different wavelengths. The signal mayalso be received at a camera, which may also comprise filters or aspectrometer. In one embodiment, the spectral discrimination usingfilters or a spectrometer may be placed after the light source ratherthan at the receiver. The receiver usually comprises one or moredetectors (optical-to-electrical conversion element) and electricalcircuitry. The receiver may also be coupled to analog to digitalconverters, particularly if the signal is to be fed to a digital device.

Referring to FIG. 25, one or more light sources 2511 may be used forillumination. In one embodiment, a transmission measurement may beperformed by directing the light source output 2511 to the region nearthe interface between the gum 2506 and dentine 2504. In one embodiment,the light may be directed using a light guide or a fiber optic. Thelight may then propagate through the dental pulp 2505 to the other side,where the light may be incident on one or more detectors or anotherlight guide to transport the signal to 2512 a spectrometer, receiver,and/or camera, for example. In one embodiment, the light source may bedirected to one or more locations near the interface between the gum2506 and dentine 2504 (in one example, could be from the two sides ofthe tooth). The transmitted light may then be detected in the occlusalsurface above the tooth using a 2512 spectrometer, receiver, or camera,for example. In another embodiment, a reflectance measurement may beconducted by directing the light source output 2511 to, for example, theocclusal surface of the tooth, and then detecting the reflectance at a2513 spectrometer, receiver or camera. Although a few embodiments forimaging the tooth are described, other embodiments and techniques mayalso be used and are intended to be covered by this disclosure. Theseoptical techniques may measure optical properties such as reflectance,transmittance, absorption, or luminescence.

In one embodiment, FIG. 28 shows that the light source and/or detectionsystem may be integrated with a dental hand-piece 2800. The hand-piece2800 may also include other dental equipment, such as a drill, pick, airspray or water cooling stream. The dental hand-piece 2800 may include ahousing 2801 and a motor housing 2802 (in some embodiments such as witha drill, a motor may be placed in this section). The end of hand-piece2803 that interfaces with the tooth may be detachable, and it may alsohave the light input and output end. The dental hand-piece 2800 may alsohave an umbilical cord 2804 for connecting to power supplies,diagnostics, or other equipment, for example.

A light guide 2805 may be integrated with the hand-piece 2800, eitherinside the housing 2801, 2802 or adjacent to the housing. In oneembodiment, a light source 2810 may be contained within the housing2801, 2802. In an alternative embodiment, the hand-piece 2800 may have acoupler 2810 to couple to an external light source 2811 and/or detectionsystem or receiver 2812. The light source 2811 may be coupled to thehand-piece 2800 using a light guide or fiber optic cable 2806. Inaddition, the detection system or receiver 2812 may be coupled to thehand-piece 2800 using one or more light guides, fiber optic cable or abundle of fibers 2807.

The light incident on the tooth may exit the hand-piece 2800 through theend 2803. The end 2803 may also have a lens system or curved mirrorsystem to collimate or focus the light. In one embodiment, if the lightsource is integrated with a tool such as a drill, then the light mayreach the tooth at the same point as the tip of the drill. The reflectedor transmitted light from the tooth may then be observed externallyand/or guided back through the light guide 405 in the hand-piece 2800.If observed externally, there may be a lens system 408 for collectingthe light and a detection system 2809 that may have one or moredetectors and electronics. If the light is to be guided back through thehand-piece 2800, then the reflected light may transmit through the lightguide 2805 back to the detection system or receiver 2812. In oneembodiment, the incident light may be guided by a fiber optic throughthe light guide 2805, and the reflected light may be captured by aseries of fibers forming a bundle adjacent to or surrounding theincident light fiber.

In another embodiment, a “clamp” design 2900 may be used as a cap overone or more teeth, as illustrated in FIG. 29. The clamp design may bedifferent for different types of teeth, or it may be flexible enough tofit over different types of teeth. For example, different types of teethinclude the molars (toward the back of the mouth), the premolars, thecanine, and the incisors (toward the front of the mouth). One embodimentof the clamp-type design is illustrated in FIG. 29 for a molar tooth2908. The C-clamp 2901 may be made of a plastic or rubber material, andit may comprise a light source input 2902 and a detector output 2903 onthe front or back of the tooth, for example.

The light source input 2902 may comprise a light source directly, or itmay have light guided to it from an external light source. Also, thelight source input 2902 may comprise a lens system to collimate or focusthe light across the tooth. The detector output 2903 may comprise adetector directly, or it may have a light guide to transport the signalto an external detector element. The light source input 2902 may becoupled electrically or optically through 2904 to a light input 2906.For example, if the light source is external in 2906, then the couplingelement 2904 may be a light guide, such as a fiber optic. Alternately,if the light source is contained in 2902, then the coupling element 2904may be electrical wires connecting to a power supply in 2906. Similarly,the detector output 2903 may be coupled to a detector output unit 2907with a coupling element 2905, which may be one or more electrical wiresor a light guide, such as a fiber optic. This is just one example of aclamp over one or more teeth, but other embodiments may also be used andare intended to be covered by this disclosure. For example, ifreflectance from the teeth is to be used in the measurement, then thelight input 2902 and detected light input 2903 may be on the same sideof the tooth.

In yet another embodiment, one or more light source ports and sensorports may be used in a mouth-guard type design. For example, oneembodiment of a dental mouth guard 3000 is illustrated in FIG. 30. Thestructure of the mouth guard 3001 may be similar to mouth guards used insports (e.g., when playing football or boxing) or in dental trays usedfor applying fluoride treatment, and the mouth guard may be made fromplastic, rubber, or any other suitable materials. As an example, themouth guard may have one or more light source input ports 3002, 3003 andone or more detector output ports 3004, 3005. Although six input andoutput ports are illustrated, any number of ports may be used.

Similar to the clamp design described above, the light source inputs3002, 3003 may comprise one or more light sources directly, or they mayhave light guided to them from an external light source. Also, the lightsource inputs 3002, 3003 may comprise lens systems to collimate or focusthe light across the teeth. The detector outputs 3004, 3005 may compriseone or more detectors directly, or they may have one or more lightguides to transport the signals to an external detector element. Thelight source inputs 3002, 3003 may be coupled electrically or opticallythrough 3006 to a light input 3007. For example, if the light source isexternal in 3007, then the one or more coupling elements 3006 may be oneor more light guides, such as a fiber optic. Alternately, if the lightsources are contained in 3002, 3003, then the coupling element 3006 maybe one or more electrical wires connecting to a power supply in 3007.Similarly, the detector outputs 3004, 3005 may be coupled to a detectoroutput unit 3009 with one or more coupling elements 3008, which may beone or more electrical wires or one or more light guides, such as afiber optic. This is just one example of a mouth guard design covering aplurality of teeth, but other embodiments may also be used and areintended to be covered by this disclosure. For instance, the position ofthe light source inputs and detector output ports could be exchanged, orsome mixture of locations of light source inputs and detector outputports could be used. Also, if reflectance from the teeth is to bemeasured, then the light sources and detectors may be on the same sideof the tooth. Moreover, it may be advantageous to pulse the light sourcewith a particular pulse width and pulse repetition rate, and then thedetection system can measure the pulsed light returned from ortransmitted through the tooth. Using a lock-in type technique (e.g.,detecting at the same frequency as the pulsed light source and alsopossibly phase locked to the same signal), the detection system may beable to reject background or spurious signals and increase thesignal-to-noise ratio of the measurement.

Other elements may be added to the human interface designs of FIGS.28-30 and are also intended to be covered by this disclosure. Forinstance, in one embodiment it may be desirable to have replaceableinserts that may be disposable. Particularly in a dentist's or doctor'soffice or hospital setting, the same instrument may be used with aplurality of patients. Rather than disinfecting the human interfaceafter each use, it may be preferable to have disposable inserts that canbe thrown away after each use. In one embodiment, a thin plastic coatingmaterial may enclose the clamp design of FIG. 29 or mouth guard designof FIG. 30. The coating material may be inserted before each use, andthen after the measurement is exercised the coating material may bepeeled off and replaced. The coating or covering material may beselected based on suitable optical properties that do not affect themeasurement, or known optical properties that can be calibrated orcompensated for during measurement. Such a design may save the dentistor physician or user considerable time, while at the same time providethe business venture with a recurring cost revenue source.

Wireless Link to the Cloud

The non-invasive dental caries measurement device may also benefit fromcommunicating the data output to the “cloud” (e.g., data servers andprocessors in the web remotely connected) via wireless means. Thenon-invasive devices may be part of a series of biosensors applied tothe patient, and collectively these devices form what might be called abody area network or a personal area network. The biosensors andnon-invasive devices may communicate to a smart phone, tablet, personaldata assistant, computer and/or other microprocessor-based device, whichmay in turn wirelessly or over wire and/or fiber optic transmit some orall of the signal or processed data to the internet or cloud. The cloudor internet may in turn send the data to dentists, doctors or healthcare providers as well as the patients themselves. Thus, it may bepossible to have a panoramic, high-definition, relatively comprehensiveview of a patient that doctors and dentists can use to assess and managedisease, and that patients can use to help maintain their health anddirect their own care.

In a particular embodiment 3100, the non-invasive measurement device3101 may comprise a transmitter 3103 to communicate over a firstcommunication link 3104 in the body area network or personal areanetwork to a receiver in a smart phone, tablet, cell phone, PDA, and/orcomputer 3105, for example. For the measurement device 3101, it may alsobe advantageous to have a processor 3102 to process some of the measureddata, since with processing the amount of data to transmit may be less(hence, more energy efficient). The first communication link 3104 mayoperate through the use of one of many wireless technologies such asBluetooth, Zigbee, WiFi, IrDA (infrared data association), wireless USB,or Z-wave, to name a few. Alternatively, the communication link 3104 mayoccur in the wireless medical band between 2360 MHz and 2390 MHz, whichthe FCC allocated for medical body area network devices, or in otherdesignated medical device or WMTS bands. These are examples of devicesthat can be used in the body area network and surroundings, but otherdevices could also be used and are included in the scope of thisdisclosure.

The personal device 3105 may store, process, display, and transmit someof the data from the measurement device 3101. The device 3105 maycomprise a receiver, transmitter, display, voice control and speakers,and one or more control buttons or knobs and a touch screen. Examples ofthe device 3105 include smart phones such as the Apple iPhones® orphones operating on the Android or Microsoft systems. In one embodiment,the device 3105 may have an application, software program, or firmwareto receive and process the data from the measurement device 3101. Thedevice 3105 may then transmit some or all of the data or the processeddata over a second communication link 3106 to the internet or “cloud”3107. The second communication link 3106 may advantageously comprise atleast one segment of a wireless transmission link, which may operateusing WiFi or the cellular network. The second communication link 3106may additionally comprise lengths of fiber optic and/or communicationover copper wires or cables.

The internet or cloud 3107 may add value to the measurement device 3101by providing services that augment the measured data collected. In aparticular embodiment, some of the functions performed by the cloudinclude: (a) receive at least a fraction of the data from the device3105; (b) buffer or store the data received; (c) process the data usingsoftware stored on the cloud; (d) store the resulting processed data;and (e) transmit some or all of the data either upon request or based onan alarm. As an example, the data or processed data may be transmitted3108 back to the originator (e.g., patient or user), it may betransmitted 3109 to a health care provider or doctor or dentist, or itmay be transmitted 3110 to other designated recipients.

Service providers coupled to the cloud 3107 may provide a number ofvalue-add services. For example, the cloud application may store andprocess the dental data for future reference or during a visit with thedentist or healthcare provider. If a patient has some sort of medicalmishap or emergency, the physician can obtain the history of the dentalor physiological parameters over a specified period of time. In anotherembodiment, alarms, warnings or reminders may be delivered to the user3108, the healthcare provider 3109, or other designated recipients 3110.These are just some of the features that may be offered, but many othersmay be possible and are intended to be covered by this disclosure. As anexample, the device 3105 may also have a GPS sensor, so the cloud 3107may be able to provide time, date, and position along with the dental orphysiological parameters. Thus, if there is a medical or dentalemergency, the cloud 3107 could provide the location of the patient tothe dental or healthcare provider 3109 or other designated recipients3110. Moreover, the digitized data in the cloud 3107 may help to movetoward what is often called “personalized medicine.” Based on the dentalor physiological parameter data history, medication or medical/dentaltherapies may be prescribed that are customized to the particularpatient. Another advantage for commercial entities may be that byleveraging the advances in wireless connectivity and the widespread useof handheld devices such as smart phones that can wirelessly connect tothe cloud, businesses can build a recurring cost business model evenusing non-invasive measurement devices.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for non-invasive measurements of dentalcaries and early detection of carious regions. However, many otherdental or medical procedures can use the near-infrared or SWIR lightconsistent with this disclosure and are intended to be covered by thedisclosure.

Section 3: Short-Wave Infrared Super-Continuum Lasers for Natural GasLeak Detection, Exploration, and Other Active Remote SensingApplications

One advantage of optical systems is that they can perform non-contact,stand-off or remote sensing distance spectroscopy of various materials.For remote sensing particularly, it may also be necessary to operate inatmospheric transmission windows. For example, two windows in the SWIRthat transmit through the atmosphere are approximately 1.4-1.8 micronsand 2-2.5 microns. In general, the near-infrared region of theelectromagnetic spectrum covers between approximately 0.7 microns (700nm) to about 2.5 microns (2500 nm). However, it may also be advantageousto use just the short-wave infrared between approximately 1.4 microns(1400 nm) and about 2.5 microns (2500 nm). One reason for preferring theSWIR over the entire NIR may be to operate in the so-called “eye safe”window, which corresponds to wavelengths longer than about 1400 nm.Therefore, for the remainder of the disclosure the SWIR will be used forillustrative purposes. However, it should be clear that the discussionthat follows could also apply to using the NIR wavelength range, orother wavelength bands.

In particular, wavelengths in the eye safe window may not transmit downto the retina of the eye, and therefore, these wavelengths may be lesslikely to create permanent eye damage from inadvertent exposure. Thenear-infrared wavelengths have the potential to be dangerous, becausethe eye cannot see the wavelengths (as it can in the visible), yet theycan penetrate and cause damage to the eye. Even if a practitioner is notlooking directly at the laser beam, the practitioner's eyes may receivestray light from a reflection or scattering from some surface. Hence, itcan always be a good practice to use eye protection when working aroundlasers. Since wavelengths longer than about 1400 nm are substantiallynot transmitted to the retina or substantially absorbed in the retina,this wavelength range is known as the eye safe window. For wavelengthslonger than 1400 nm, in general only the cornea of the eye may receiveor absorb the light radiation.

The SWIR wavelength range may be particularly valuable for identifyingmaterials based on their chemical composition because the wavelengthrange comprises overtones and combination bands for numerous chemicalbonds. As an example, FIG. 32 illustrates some of the wavelength bandsfor different chemical compositions. In 100 is plotted wavelength rangesin the SWIR (between 1400 and 2500 nm) for different chemical compoundsthat have vibrational or rotational resonances, along with whether thebands are overtone or combination bands. Numerous hydro-carbons arerepresented, along with oxygen-hydrogen and carbon-oxygen bonds. Thus,gases, liquids and solids that comprise these chemical compounds mayexhibit spectral features in the SWIR wavelength range. In a particularembodiment, the spectra of organic compounds may be dominated by the C—Hstretch. The C—H stretch fundamental occurs near 3.4 microns, the firstovertone is near 1.7 microns, and a combination band occurs near 2.3microns.

One embodiment of remote sensing that is used to identify and classifyvarious materials is so-called “hyper-spectral imaging.” Hyper-spectralsensors may collect information as a set of images, where each imagerepresents a range of wavelengths over a spectral band. Hyper-spectralimaging may deal with imaging narrow spectral bands over anapproximately continuous spectral range. As an example, inhyper-spectral imaging the sun may be used as the illumination source,and the daytime illumination may comprise direct solar illumination aswell as scattered solar (skylight), which is caused by the presence ofthe atmosphere. However, the sun illumination changes with time of day,clouds or inclement weather may block the sun light, and the sun lightis not accessible in the night time. Therefore, it would be advantageousto have a broadband light source covering the SWIR that may be used inplace of the sun to identify or classify materials in remote sensing orstand-off detection applications.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. As used throughout this disclosure, the term “spectroscopy”means that a tissue or sample is inspected by comparing differentfeatures, such as wavelength (or frequency), spatial location,transmission, absorption, reflectivity, scattering, refractive index, oropacity. In one embodiment, “spectroscopy” may mean that the wavelengthof the light source is varied, and the transmission, absorption orreflectivity of the tissue or sample is measured as a function ofwavelength. In another embodiment, “spectroscopy” may mean that thewavelength dependence of the transmission, absorption or reflectivity iscompared between different spatial locations on a tissue or sample. Asan illustration, the “spectroscopy” may be performed by varying thewavelength of the light source, or by using a broadband light source andanalyzing the signal using a spectrometer, wavemeter, or opticalspectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium. In anotherembodiment, the mid-infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium and/orthulium. In one embodiment, the “pump laser” may be a fiber laser, asolid state laser, a laser involving a nonlinear crystal, an opticalparametric oscillator, a semiconductor laser, or a plurality ofsemiconductor lasers that may be multiplexed together. In anotherembodiment, the “pump laser” may be coupled to the gain medium by usinga fiber coupler, a dichroic mirror, a multiplexer, a wavelength divisionmultiplexer, a grating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth of at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, parametricamplification, the Raman effect, modulational instability, andself-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

As used throughout this disclosure, the term “remote sensing” mayinclude the measuring of properties of an object from a distance,without physically sampling the object, for example by detection of theinteractions of the object with an electromagnetic field. In oneembodiment, the electromagnetic field may be in the optical wavelengthrange, including the infrared or SWIR. One particular form of remotesensing may be stand-off detection, which may range from non-contact upto hundreds of meters away, for example.

Remote Sensing of Natural Gas Leaks

Natural gas may be a hydro-carbon gas mixture comprising primarilymethane, with other hydro-carbons, carbon dioxide, nitrogen and hydrogensulfide. Natural gas is important because it is an important energysource to provide heating and electricity. Moreover, it may also be usedas fuel for vehicles and as a chemical feedstock in the manufacture ofplastics and other commercially important organic chemicals. Althoughmethane is the primary component of natural gas, to uniquely identifynatural gas through spectroscopy requires monitoring of both methane andethane. If only methane is used, then areas like cow pastures could bemistaken for natural gas fields or leaks. More specifically, the typicalcomposition of natural gas is as follows:

Component Range (mole %) Methane  87.0-96.0 Ethane  1.5-5.1 Propane 0.1-1.5 Iso-butane 0.01-0.3 Normal-butane 0.01-0.3 Iso-pentaneTrace-0.14 Normal-pentane Trace-0.04 Hexanes plus Trace-0.06 Nitrogen 0.7-5.6 Carbon dioxide  0.1-1.0 Oxygen 0.01-0.1 Hydrogen Trace-0.02

As one example of remote sensing of natural gas, a helicopter oraircraft may be flown at some elevation. The light source for remotesensing may direct the light beam toward the ground, and the diffusereflected light may then be measured using a detection system on theaircraft. Thus, the helicopter or aircraft may be sampling a column areabelow it for natural gas, or whatever the material of interest is. Inyet another embodiment, the column may sense aerosols of various sorts,as an example. Various kinds of SWIR light sources will be discussedlater in this disclosure. The detection system may comprise, in oneembodiment, a spectrometer followed by one or more detectors. In anotherembodiment, the detection system may be a dispersive element (examplesinclude prisms, gratings, or other wavelength separators) followed byone or more detectors or detector arrays. In yet another embodiment, thedetection system may comprise a gas-filter correlation radiometer. Theseare merely specific examples of the detection system, but combinationsof these or other detection systems may also be used and arecontemplated within the scope of this disclosure. Also, the use ofaircraft is one particular example of a remote sensing system, but othersystem configurations may also be used and are included in the scope ofthis disclosure. For example, the light source and detection system maybe placed in a fixed location, and for reflection the light source anddetectors may be close to one another, while for transmission the lightsource and detectors may be at different locations. In yet anotherembodiment, the system could be placed on a vehicle such as anautomobile or a truck, or the light source could be placed on onevehicle, while the detection system is on another vehicle. If the lightsource and detection system are compact and lightweight, they might evenbe carried by a person in the field, either in their hands or in abackpack.

Both methane and ethane are hydro-carbons with unique spectralsignatures. For example, ethane is C2H6, while methane is CH4. Also,methane and ethane have infrared absorption bands near 1.6 microns, 2.4microns, 3.3 microns and 7 microns. It should be noted that theapproximately 7 micron lines cannot be observed generally due toatmospheric absorption. Although the fundamental lines near 3.3 micronsare stronger absorption features, the light sources and detectors in themid-infrared may be more difficult to implement. Hence, the focus hereis on observing the SWIR lines that fall in atmospheric transparencywindows.

FIG. 33 illustrates the absorption spectra for methane (FIG. 33A) andethane (FIG. 33B) (from http://vpl.astro.washington.edu/spectra). Thecurves 3300 plot on a linear scale the absorption cross-section versuswavelength (in microns) for various methane lines. The curve 3301 coversthe wavelength range between approximately 1.5-16 microns, while thecurves below provide blown-up views of different wavelength ranges (3302for approximately 1.62-1.7 microns, 3303 for approximately 1.7-1.84microns, 3304 for approximately 2.15-2.45 microns, and 3305 forapproximately 2.45-2.65 microns). The curves 3302 and 3303 fall withinabout the first SWIR atmospheric transmission window betweenapproximately 1.4-1.8 microns, while the curves 3304 and 3305 fallwithin the second SWIR atmospheric transmission window betweenapproximately 2-2.5 microns. As can be seen, there are numerous spectralfeatures for identifying methane in the SWIR. In addition, there areeven stronger features near 3.4-3.6 microns and around 7-8 microns,although these require different light sources and detection systems.

FIG. 33B illustrates the absorption spectra for ethane. The curves 3350plot on a linear scale the absorption cross-section versus wavelength(in microns) for various ethane lines. The curve 3351 covers thewavelength range between approximately 1.5-16 microns, while the curve3352 expands the scale between about 1.6-3.2 microns. The features 3353fall within about the first SWIR atmospheric transmission window betweenapproximately 1.4-1.8 microns, while the features 3354 and 3355 fallwithin the second SWIR atmospheric transmission window betweenapproximately 2-2.5 microns. There are distinct spectral features foridentifying ethane as well in the SWIR. In addition, there are evenstronger features near 3.4-3.6 microns and around 7 microns.

For detecting natural gas leaks, a SWIR light source and a detectionsystem could be used in transmission or reflection. The area surroundingthe source or natural gas pipeline may be surveyed, and the detectionsystem may monitor the methane and ethane concentration, or even thepresence of these two gases. The region may be scanned to cover an arealarger than the laser beam. Also, if a certain quantity of natural gasis detected, an alarm may be set-off to alert the operator or peoplenearby. This is just one example of the natural gas leak detection, butother configurations and techniques may be used and are intended to becovered by this disclosure.

Natural gas leak detection is one example where active remote sensing orhyper-spectral imaging can be used to detect hydro-carbons or organiccompounds. However, there are many other examples where the techniquemay be used to perform reflectance spectroscopy of organic compounds,and these are also intended to be covered by this disclosure. In oneparticular embodiment, alkanes may be detected, where alkanes arehydro-carbon molecules comprising single carbon-carbon bonds. Alkaneshave the general formula CnH2n+2 and are open chain, aliphatic ornon-cyclic molecules. Below are examples of some of the alkanes, whichinclude methane and ethane, as well as more complicated compounds.

Formula Methane CH₄ Ethane C₂H₆ Propane C₃H₈ Butane C₄H₁₀ Pentane C₅H₁₂Hexane C₆H₁₄ Heptane C₇H₁₆ Octane C₈H₁₈ Nonane C₉H₂₀ Decane C₁₀H₂₂Paraffin C₂₀₊H₄₂₊ Polyethylene (C₂H₄)_(n) or (LDPE, HDPE) (CH₂CH₂)_(n)Polyvinylchloride (C₂H₃Cl)_(n) or (PVC) (CHClCH₂)_(n) Polypropylene(C₃H₅)_(n) or {CH(CH₃)CH₂}_(n) Polyethylene terephthalate C₁₀H₈O₄ or(PETE) {(CO₂)₂C₆H₄(CH₂)₂}_(n) Nylon (polyamide) C₁₂H₂₄O₄N₂ or{C₁₀H₂₂(CO₂)₂(NH)₂}_(n)

FIG. 34 illustrates the reflectance spectra 3400 for some members of thealkane family plus paraffin. The vertical lines indicate positions ofconstant wavelength and are aligned with apparent absorptions in themethane spectrum at 1.19, 1.67, 2.32, 3.1, 4.23 and 4.99 microns. Thespectra ore offset to enable easier viewing, and the offsets are of thefollowing amounts: 3401 methane 4.1; 3402 ethane 3.6; 3403 propane 3.3;3404 butane 2.8; 3405 pentane 2.3; 3406 hexane 2.0; 3407 heptane 1.5;3408 octane 1.2; 3409 nonane 0.85; 3410 decane 0.4; and 3411 paraffin0.05. The reflectance of alkanes in the near-infrared may be dominatedby absorptions due to combinations and overtones of bands at longerwavelengths. Although this wavelength range is mostly unexplored byorganic spectroscopists, the near-infrared may be valuable forterrestrial and planetary remote sensing studies. Alkanes may have thefundamental absorptions due to a variety of C—H stretches betweenapproximately 3.3-3.5 microns. The first overtone may be a relativelydeep triplet near 1.7 microns. This triplet appears in most of theseries, but the exact wavelength position may move. Another absorptionband may be present near 1.2 microns, and this is likely the secondovertone of the C—H stretch. The third C—H stretch overtone is near 0.9microns. There is yet another near-infrared feature near 1.396 microns,which may correspond to the combinations of the first overtone of theC—H stretch with each of the two C—H band positions at approximately1.35 microns and 1.37 microns. Moreover, there may be complexabsorptions between 2.2-2.5 microns. For example, there may be a numberof narrow individual absorption bands atop an overall absorption suiteabout 0.3 microns wide. A few absorption lines retain their location formost of the series 300, notably the 2.311 micron and 2.355 micronabsorptions. This wavelength window may have multiple combinations andovertones, including contributions from the C—H stretch, CH3 asymmetricbend combination, and C—H stretch/CH3 symmetric bend combination.

Remote Sensing for Natural Gas Exploration

In addition to remote sensing to detect natural gas leaks, the same orsimilar system could also be used to explore for natural gas fields,whether under land or under water. Whereas a natural gas leak from apipeline or building may be above the ground or only a few meters belowthe ground, natural gas exploration may occur for gas and oil that aremuch further below the ground, or under the water in a bay, lake, sea orocean. For example, the exploration for natural gas and oil may beperformed by determining the reflectance spectra of surface anomalies.The surface manifestations of oil and gas reservoirs may be used to mapthe petroleum potential of an area, particularly related to the seepageof oil and gas to the surface along faults or imperfect reservoir seals.The visible products of such seepage (e.g., oil and tar deposits) aregenerally referred to as macro-seeps, whereas the invisible gaseousproducts may be referred to as micro-seeps.

As illustrated by 3500 in FIG. 35, micro-seepages may result from thevertical movement of hydrocarbons 3501 from their respective reservoirsto the surface. These hydrocarbon micro-seepages involve buoyant,relatively rapid, vertical ascent of ultra-small bubbles of lighthydrocarbons (primarily methane through the butanes) through a networkof interconnected, groundwater-filled joints and bedding planes (3501).One of the assumptions required for micro-seepage to occur is that arock column, including the seal rock, comprises extensive interconnectedfractures or micro-fracture systems.

Direct detection methods may involve measurements of hydrocarbons,either in the form of oil accumulations or concentrations of escapingvapors, such as methane through butane. In addition, there are alsoindirect methods that may involve the measurement of secondaryalternations that arise from the seepage of the hydrocarbons. Forinstance, hydrocarbon-induced alterations may include microbialanomalies, mineralogical changes, bleaching of red beds, clay mineralalterations, and electrochemical changes. These alterations occurbecause leaking hydrocarbons set up near-surface oxidation and/orreduction zones that favor the development of a diverse array ofchemical and mineralogical changes, c.f. 3502 in FIG. 35. Suchalterations 3502 may be distinct from adjacent rocks and, thus, may insome instance be detectable by various remote sensing techniques.

The diagnostic spectral features of methane and crude oil may comprisefour distinct hydrocarbon absorption bands. For example, two bands near1.18 microns and 1.38 microns may be narrow and sharply defined,although they may also be fairly weak. The other two spectral featuresmay be near 1.68-1.72 microns and 2.3-2.45 microns; these bands may bebroader, but they are also stronger than the previous two bands. Thebands near 1.7 microns and 2.3 microns are spectral overtones orcombinations of C—H vibrational modes. Moreover, hydrocarbon inducedalterations associated with indirect detection may express themselves ina variety of spectral changes, such as mineralogical changes (calciumcarbonate mineralization, near 2.35 microns), bleaching of red beds(near 1 micron), and clay minerals alterations (near 2.2 microns), amongother changes.

Various field tests have been conducted that verify the spectralsignatures associated with natural gas fields, either land-based orwater-based (e.g., in bays). In one example shown in FIG. 36A, thereflectance spectra 3600 was collected for different locations betweenapproximately 2 microns and 2.4 microns. In 3601 the reflectance isplotted versus wavelength for locations with gas fields, while in 3602the reflectance is plotted for locations without gas fields. Themacroscopic features of the reflectance spectra of surface soils showtwo broad absorption bands near 2.2 microns and 2.33 microns withcomplex shapes. The slightly positive slope in the region of 2.3-2.4microns with natural gas suggests that hydrocarbons are overriding thespectral signature of clays in this region.

In yet another embodiment, field tests were conducted over a widerspectra range from approximately 0.5 microns to 2.5 microns (FIG. 36B).As the curve 3650 illustrates, two absorption features are found for thehydrocarbon spectral reflectance curve: one near 1.725 microns 3651 anda double absorption at approximately 2.311-2.36 microns 3652. Thus, inthese two field trial examples, oil-gas reservoir areas wereidentifiable using feature bands of 1650-1750 nm and 2000-2400 nm. Inaddition, the remote sensing method may be used for off-shore oil andgas exploration and marine pollution investigation, to name just a fewexamples.

Other Uses of Active Remote Sensing or Hyperspectral Imaging

Active and/or hyper-spectral remote sensing may be used in a wide arrayof applications. Although originally developed for mining and geology(the ability of spectral imaging to identify various minerals may beideal for the mining and oil industries, where it can be used to lookfor ore and oil), hyper-spectral remote sensing has spread to fields asdiverse as ecology and surveillance. The table below illustrates some ofthe applications that can benefit from hyper-spectral remote sensing.

Atmosphere water vapor, cloud properties, aerosols Ecology chlorophyll,leaf water, cellulose, pigments, lignin Geology mineral and soil typesCoastal Waters chlorophyll, phytoplankton, dissolved organic materials,suspended sediments Snow/Ice snow cover fraction, grainsize. meltingBiomass Burning subpixel temperatures, smoke Commercial mineral (oil)exploration, agriculture and forest production

In one embodiment, near-infrared imaging spectroscopy data may be usedto create qualitative images of thick oil or oil spills on water. Thismay provide a rapid remote sensing method to map the locations of thickparts of an oil spill. While color imagery may show locations of thickoil, it is difficult to assess relative thickness or volume with justcolor imagery. As an example, FIG. 37 illustrates the reflectancespectra 3700 of a sample of oil emulsion from the Gulf of Mexico 2010oil spill. Curve 3701 is a 4 mm thickness of oil, while curve 3702 is a0.5 mm thickness. Whereas the data in the visible hardly changes withoil thickness, in the near-infrared the change in reflectance spectra ismuch more dependent on the oil thickness. The data shows, for example,the C—H features near 1.2 microns 3703, 1.73 microns 3704, and 2.3microns 3705. Thus, in the infrared wavelengths, both the reflectancelevels and absorption features due to organic compounds may vary instrength with oil thickness.

Remote sensing may also be used for geology and mineralogy mapping orinspection. FIG. 38 shows the reflectance spectra 3800 for somerepresentative minerals that are major components of rocks and soils. Ininorganic materials such as minerals, chemical composition andcrystalline structure may control the shape of the spectral curve andthe locations of absorption bands. Wavelength-specific absorption mayarise from particular chemical elements or ions and the geometry ofchemical bonds between elements, which is related to the crystalstructure. In hematite 3801, the strong absorption in the visible may becaused by ferric iron. In calcite 3805, the carbonate ion may beresponsible for the series of absorption bands between 1.8 and 2.4microns. Kaolinite 3804 and montmorillonite 3802 are clay mineralscommon in soils. The strong absorption near 1.4 microns in both spectra,along with a weak 1.9 micron band in kaolinite arise from the hydroxideions, while the stronger 1.9 micron band in montmorillonite may becaused by bound water molecules in the hydrous clay. In contrast tothese spectra, orthoclase feldspar 3803, a dominant mineral in granite,shows very little absorption features in the visible or infrared.

Remote sensing or hyper-spectral imaging may also be used foragriculture as well as vegetation monitoring. For example,hyper-spectral data may be used to detect the chemical composition ofplants, which can be used to detect the nutrient and water status ofcrops. FIG. 39 illustrates the reflectance spectra 3900 of differenttypes of green vegetation compared with dry, yellowed grass. In thevisible spectra, the shape may be determined by absorption effects fromchlorophyll and other leaf pigments. The reflectance rises rapidlyacross the boundary between red and infrared wavelengths, which may bedue to interactions with the internal cellular structure of leaves. Leafstructure may vary significantly between plant species, as well as fromplant stress. Beyond 1.3 microns the reflectance decreases withincreasing wavelength, except for two water absorption bands near 1.4microns and 1.9 microns. Illustrated in FIG. 39 are the reflectance forgreen grass 3901, walnut tree canopy 3902, fir tree 3903 and senescent3904, which is dry, yellowed grass.

Active remote sensing may also be used to measure or monitor gases inthe earth's atmosphere, including greenhouse gases, environmentalpollutants and aerosols. For instance, greenhouse gases are those thatcan absorb and emit infrared radiation: In order, the most abundantgreenhouse gasses in the Earth's atmosphere are: water vapor (H2O),carbon dioxide (CO2), methane (CH4), nitrous oxide (N2O) and ozone (O3).FIG. 40 shows the atmospheric absorption and scattering of greenhousegases 4000 at different wavelengths. Included in this figure are thetotal absorption and scattering 4001, along with the breakdown by majorcomponents: water vapor 4002, carbon dioxide 4003, oxygen and ozone4004, methane 4005, and nitrous oxide 4006. Also shown is the Rayleighscattering 4007 through the atmosphere, which dominates at shorterwavelengths, particularly wavelengths shorter than about 1 micron. Inone embodiment, environmental concerns of climate change have led to theneed to monitor the level of carbon dioxide in the atmosphere, and thismay be achieved, for example, by performing spectroscopy in the vicinityof 1.6 microns and 2 microns.

In yet another embodiment, different building materials may beidentified and distinguished from surrounding vegetation and forestry.FIG. 41 overlays different reflectance data 4100 for samples catalogedin the ASTER spectra library (http://speclib.jpl.nasa.gov). This libraryhas been made available by NASA as part of the Advanced SpaceborneThermal Emission and Reflection Radiometer, ASTER, imaginginstrumentation program. Included in this and other libraries arereflection spectra of natural and man-made materials, includingminerals, rocks, soils, water and snow. In FIG. 41 several spectra areincluded over the SWIR atmospheric transmission bands, and the waterabsorption between approximately 1.8 and 2 microns has been blocked out(features in there are either due to water or would be masked by theatmospheric moisture). Included in the graph are the spectra for silvermetallic paint 4101, light brown loamy sand 4102, constructionconcrete-1 4103, construction concrete-cement 4104, gypsum 4105,asphaltic concrete 4106, construction concrete-bridges 4107, grass 4108and conifer trees 4109. As an example, active remote sensing can be usedto distinguish different concrete structures, including roadways,buildings, and reinforced structures such as bridges. Also, buildingmaterials such as gypsum, painted structures, plywood, and concrete ofvarious sorts, may be distinguished from plant life, soil and trees.Thus, beyond three dimensional imaging, this can add a fourthdimension—namely, identification of objects based on their chemicalsignature.

In a further embodiment, remote sensing or hyper-spectral imaging mightbe used for process control in a factory or manufacturing setting,particularly when the measurements are to be made at some stand-off orremote distance. As an example, plastics show distinct signatures in theSWIR, and process control may be used for monitoring the manufacture ofplastics. Alternately, SWIR light could be used to see through plastics,since the signature for plastics can be subtracted off and there arelarge wavelength windows where the plastics are transparent. FIG. 42illustrates the absorbance 4200 for two common plastics: polyethylene4201 and polystyrene 4202. Because of the hydro-carbon bonds, there areabsorption features near 1.7 microns and 2.2-2.5 microns (c.f.,discussion on alkanes). In general, the absorption bands in the nearinfrared are due to overtones and combination bands for variousfunctional group vibrations, including signals from C—H, O—H, C═O, N—H,—COOH, and aromatic C—H groups. It may be difficult to assign anabsorption band to a specific functional group due to overlapping ofseveral combinations and overtones. However, with advancements incomputational power and chemometrics or multivariate analysis methods,complex systems may be better analyzed. In one embodiment, usingsoftware analysis tools the absorption spectrum may be converted to itssecond derivative equivalent. The spectral differences may permit afast, accurate, non-destructive and reliable identification ofmaterials. Although particular derivatives are discussed, othermathematical manipulations may be used in the analysis, and these othertechniques are also intended to be covered by this disclosure.

In another specific embodiment, experiments have been performed forstand-off detection of solid targets with diffuse reflectionspectroscopy using a fiber-based super-continuum source (furtherdescribed herein). In particular, the diffuse reflection spectrum ofsolid samples such as explosives (TNT, RDX, PETN), fertilizers (ammoniumnitrate, urea), and paints (automotive and military grade) have beenmeasured at stand-off distances of 5 m. Although the measurements weredone at 5 m, calculations show that the distance could be anywhere froma few meters to over 150 m. These are specific samples that have beentested, but more generally other materials (particularly comprisinghydro-carbons) could also be tested and identified using similarmethods. The experimental set-up 4300 for thereflection-spectroscopy-based stand-off detection system is shown inFIG. 43, while details of the SC source 4301 are described later in thisdisclosure (c.f. FIGS. 20,21, and 23). First, the diverging SC output iscollimated to a 1 cm diameter beam using a 25 mm focal length, 90degrees off-axis, gold coated, parabolic mirror 4302. To reduce theeffects of chromatic aberration, refractive optics are avoided in thesetup. All focusing and collimation is done using metallic mirrors thathave almost constant reflectivity and focal length over the entire SCoutput spectrum. The sample 4304 is kept at a distance of 5 m from thecollimating mirror 4302, which corresponds to a total round trip pathlength of 10 m before reaching the collection optics 4305. A 12 cmdiameter silver coated concave mirror 4305 with a 75 cm focal length iskept 20 cm to the side of the collimation mirror 4302. The mirror 4305is used to collect a fraction of the diffusely reflected light from thesample, and focus it into the input slit of a monochromator 4306. Thus,the beam is incident normally on the sample 4304, but detected at areflection angle of tan−1(0.2/5) or about 2.3 degrees. Appropriate longwavelength pass filters mounted in a motorized rotating filter wheel areplaced in the beam path before the input slit 4306 to avoid contributionfrom higher wavelength orders from the grating (300 grooves/mm, 2 μmblaze). The output slit width is set to 2 mm corresponding to a spectralresolution of 10.8 nm, and the light is detected by a 2 mm×2 mm liquidnitrogen cooled (77K) indium antimonide (InSb) detector 4307. Thedetected output is amplified using a trans-impedance pre-amplifier 4307with a gain of about 105V/A and connected to a lock-in amplifier 4308setup for high sensitivity detection. The chopper frequency is 400 Hz,and the lock-in time constant is set to 100 ms corresponding to a noisebandwidth of about 1 Hz. These are exemplary elements and parametervalues, but other or different optical elements may be used consistentwith this disclosure.

Three sets of solid samples are chosen to demonstrate the stand-offdiffuse reflection spectra measurement in the laboratory. The first setcomprises ‘Non-hazardous Explosives for Security Training and Testing’(NESTT) manufactured by the XM Division of VanAken International. Thesesamples contain small amounts of explosives deposited on an inert fusedsilica powder substrate. The experiments are conduced with the followingsamples—trinitrotoluene (TNT), research department explosive (RDX),Pentaerythritol tetranitrate (PETN), and potassium nitrate. The TNT, RDXand potassium nitrate NESTT samples have 8% (by weight) explosives,while the PETN sample has 4%.

The second sample set consists of ammonium nitrate, urea, gypsum, andpinewood. Ammonium nitrate and urea are common fertilizers, but are alsooften used as explosives. These samples are ground to a fine powder in amortar and pestle, and filled to a depth of about 5 mm in a shallowglass container. We also measure the reflection spectrum of a 10 cmdiameter×0.5 cm thick Gypsum (CaSO4.2H2O) disk and a 5 cm×5 cm×0.5 mpiece of pine wood, since these samples are relevant for the remotesensing community (minerals and vegetation).

The final set of samples is selected to distinguish between commercialautomotive and military vehicle paints based on their reflectionsignatures. Red, black, and green acrylic based spray paints areobtained from an auto supply store and sprayed 3 coats on differentareas of a sanded Aluminum block to make the automotive paint samples.The sample of the military paint consisted of an Aluminum block coatedwith a chemical agent resistant coating (CARC) green paint.

The chemical structure and molecular formula of the 4 NESTT samples areshown in FIG. 44 (4401, 4402, 4403, 4404), while the absorbance spectraobtained using the SC source are shown below in the same FIG. 4405,4406, 4407, 4408). For each sample, the positions of thestrongest/unique peaks have been labeled for clarity. TNT 4401, 4405belongs to a class of compounds known as nitro-aromatics, in which thecarbon directly attached to the nitro (NO2) group is part of an aromaticring. The strongest peaks in the spectrum observed at 3230 nm and 3270nm are due to the fundamental C—H stretching vibrations in the aromaticring. There are also features between 2200-2600 nm, which may arise fromthe combination between the C—H stretch and C—H bend vibrations. RDX4402, 4406 belongs to the nitramines class containing the N—NO2 bond andalso has multiple features in the 3200-3500 nm band due to the C—Hstretch vibrations. This spectrum also contains the C—H combinationbands from 2200-2600 nm. PETN 4403, 4407 is classified as a nitrateester containing the C—O—NO2 bond, and its reflection spectrum ischaracterized by a triplet of peaks at 3310 nm, 3350 nm and 3440 nm dueto the C—H stretch vibration from the aliphatic groups. The C—Hcombination band is also present from 2200-2600 nm. Potassium nitrate4404, 4408 being an inorganic compound does not contain any absorptionfeatures due to the C—H bond present in the other three samples.Instead, the unique spectral feature for this sample is a pair of peaksat 3590 nm and 3650 nm, which arise due to the first overtone of theasymmetric N—O stretching vibration of the nitrate ion (NO3-).

FIG. 45A illustrates the reflection spectra 4500 for gypsum 4501,pinewood 4502, ammonium nitrate 4503 and urea 4504. The predominantspectral features in the gypsum 4501 (CaSO4.2H2O) reflectance occur dueto the fundamental as well as combination bands of the water moleculenear 1450 nm, 1750 nm, 1940 nm and 2860 nm. In addition, small dips inthe spectrum at 2220, 2260 and 2480 nm which arise due to the firstovertone of the S—O bending vibration. Moreover, the valley at 3970 nmoccurs due to the first overtone of the —O—S—O stretching vibration ofthe sulfate (SO42-) ion. The pine wood spectrum 4502 comprises of bandsdue to its main constituents—cellulose, lignin and water. The valleys at1450 nm, 1920 nm and 2860 nm are attributed to water. The dip at 2100 nmis due to the first overtone of the C—O asymmetric stretch, the one at2270 nm due to the combination band of O—H and C—H, and the one at 2490nm due to combination band of C—H and C—O. Finally, the broad featurearound 3450 nm is due to the C—H stretching vibration. The ammoniumnitrate (NH4NO3) spectrum 4503 has three prominent features in thenear-IR region. The dip at 1270 nm is due to the combination of N—Hstretching and N—H bending vibrations, while the dip at 1570 nm is dueto the first overtone of N—H stretch. The doublet at 2050 nm and 2140 nmis possibly due to the second overtone of the N—H bending vibrations,while the fundamental N—H stretch appears as a broad feature around 3000nm. Urea (NH2)2CO 4504 has two amide (—NH2) groups joined by a carbonyl(C═O) functional group. The absorption line at 1490 nm occurs due to thethird overtone of the C═O stretching vibration while the line at 1990 nmis due to the second overtone of the same.

FIG. 45B shows the reflection spectra 4550 for three commercialautomotive paints 4551, 4552, 4553 and military grade CARC (chemicalagent resistant coating) paint 4554. The paints consist of a complexmixture of many different chemicals, and, hence, it is very difficult toidentify individual absorption lines. Since all four paints contain avariety of organic compounds, features are observed between 3200-3500 nmfrom the C—H stretch and from 2200-2600 nm due to the C—H stretch andC—H bond combination band. However, the primary difference between theautomotive 45451, 4552, 4553 and CARC paint 4554 is the presence of astrong dip between 1200-1850 nm in the latter, which might be attributedto the absorption from Cobalt chromite—a green pigment found inCARC-green.

Thus, FIGS. 44 and 45 show that various materials, including explosives,fertilizers, vegetation, and paints have features in the near-infraredand SWIR that can be used to identify the various samples. Althoughstronger features are found in the mid-infrared, the near-infrared maybe easier to measure due to higher quality detection systems, moremature fiber optics and light sources, and transmission throughatmospheric transmission windows. Because of these distinct spectralsignatures, these materials could also be detected using active remotesensing or hyper-spectral imaging, as described in this disclosure.These are just particular samples that have been tested at stand-offdistances, but other materials and samples may also be identified usingthe SWIR remote sensing or hyper-spectral imaging methods, and thesesamples are also intended to be covered within this disclosure. As justanother example, illicit drugs may be detectable using remote sensing orhyper-spectral imaging. FIG. 46 shows the mid-wave infrared andlong-wave infrared absorption spectra 1500 for various illicit drugs.The absorbance for cocaine 4601, methamphetamine 4602, MDMA (ecstasy)4603, and heroin 4604 are plotted versus wavelength from approximately2.5-20 microns. Although the fundamental resonances for these drugs maylie in the longer wavelength regions, there are corresponding overtonesand combination bands in the SWIR and near-infrared wavelength range.Therefore, the active remote sensing or hyper-spectral imagingtechniques described herein may also be applicable to detecting illicitdrugs from aircraft, vehicles, or hand held devices.

Detection Systems

As discussed earlier, the active remote sensing system or hyper-spectralimaging system may be on an airborne platform, mounted on a vehicle, astationary transmission or reflection set-up, or even held by a humanfor a compact system. For such a system, there are fundamentally twohardware parts: the transmitter or light source and the detectionsystem. Between the two, perhaps in a transmission or reflectionsetting, may be the sample being tested or measured. Moreover, theoutput from the detection system may go to a computational system,comprising computers or other processing equipment. The output from thecomputational system may be displayed graphically as well as withnumerical tables and perhaps an identification of the materialcomposition. These are just some of the parts of the systems, but otherelements may be added or be eliminated, and these modifiedconfigurations are also intended to be covered by this disclosure.

By use of an active illuminator, a number of advantages may be achieved.First, the variations due to sunlight and time-of-day may be factoredout. The effects of the weather, such as clouds and rain, might also bereduced. Also, higher signal-to-noise ratios may be achieved. Forexample, one way to improve the signal-to-noise ratio would be to usemodulation and lock-in techniques. In one embodiment, the light sourcemay be modulated, and then the detection system would be synchronizedwith the light source. In a particular embodiment, the techniques fromlock-in detection may be used, where narrow band filtering around themodulation frequency may be used to reject noise outside the modulationfrequency. In an alternate embodiment, change detection schemes may beused, where the detection system captures the signal with the lightsource on and with the light source off. Again, for this system thelight source may be modulated. Then, the signal with and without thelight source is differenced. This may enable the sun light changes to besubtracted out. In addition, change detection may help to identifyobjects that change in the field of view. In the following someexemplary detection systems are described.

In one embodiment, a SWIR camera or infrared camera system may be usedto capture the images. The camera may include one or more lenses on theinput, which may be adjustable. The focal plane assemblies may be madefrom mercury cadmium telluride material (HgCdTe), and the detectors mayalso include thermo-electric coolers. Alternately, the image sensors maybe made from indium gallium arsenide (InGaAs), and CMOS transistors maybe connected to each pixel of the InGaAs photodiode array. The cameramay interface wirelessly or with a cable (e.g., USB, Ethernet cable, orfiber optics cable) to a computer or tablet or smart phone, where theimages may be captured and processed. These are a few examples ofinfrared cameras, but other SWIR or infrared cameras may be used and areintended to be covered by this disclosure.

In another embodiment, an imaging spectrometer may be used to detect thelight received from the sample. For example, FIG. 47A shows a schematicdiagram 4700 of the basic elements of an imaging spectrometer. The inputlight 4701 from the sample may first be directed by a scanning mirrorand/or other optics 4702. An optical dispersing element 4703, such as agrating or prism, in the spectrometer may split the light into manynarrow, adjacent wavelength bands, which may then be passed throughimaging optics 4704 onto one or more detectors or detector arrays 4705.Some sensors may use multiple detector arrays to measure hundreds ofnarrow wavelength bands.

An example of a typical imaging spectrometer 4750 used in hyper-spectralimaging systems is illustrated in FIG. 47B. In this particularembodiment, the input light may be directed first by a tunable mirror4751. A front lens 4752 may be placed before the entrance slit 4753 andthe collector lens 4754. In this embodiment, the dispersing element is aholographic grating with a prism 4755, which separates the differentwavelength bands. Then, a camera lens 4756 may be used to image thewavelengths onto a detector or camera 4757.

FIGS. 47A and 47B provide particular examples, but some of the elementsmay not be used, or other elements may be added, and these embodimentsare also intended to be covered by this disclosure. For instance, ascanning spectrometer may be used before the detector, where a gratingor dispersive element is scanned to vary the wavelength being measuredby the detector. In yet another embodiment, filters may be used beforeone or more detectors to select the wavelengths or wavelength bands tobe measured. This may be particularly useful if only a few bands orwavelengths are to be measured. The filters may be dielectric filters,Fabry-Perot filters, absorption or reflection filters, fiber gratings,or any other wavelength selective filter. In an alternate embodiment, awavelength division multiplexer, WDM, may be used followed by one ormore detectors or detector arrays. One example of a planar wavelengthdivision multiplexer may be a waveguide grating router or an arrayedwaveguide grating. The WDM may be fiber coupled, and detectors may beplaced directly at the output or the detectors may be coupled throughfibers to the WDM. Some of these components may also be combined withthe configurations in FIGS. 47A and 47B.

While the above detection systems could be categorized as single pathdetection systems, it may be advantageous in some cases to usemulti-path detection systems. In one embodiment, when the aim is tomeasure particular gases or material (rather than identify out of alibrary of materials), it may advantageous to use gas-filter correlationradiometry (GFCR), such as 4800 in FIG. 48. A GFCR is a detection systemthat uses a sample of the gas of interest as a spectral filter for thegas. As shown in FIG. 48, the incoming radiation 4801 may first bepassed through a narrow band pass filter 4802. The beam may then besplit by a beam splitter 4803 along two paths; one path comprising a gascell filled with the gas of interest 4804 (known as the correlationcell) and the other path comprising no gas 4805. The light from eachpath may then be measured using two detectors 4806, 4807, and thesignals may then be analyzed 4808. The difference in the transmissionalong the two paths may correspond primarily to the absorption of thegas along the correlation cell path. This GFCR configuration may beadvantageous, for example, in the detection of natural gas. Since thegoal is to measure methane and ethane, the correlation cells may containthese gases, either in combination or separately. Although a particularconfiguration for the GFCR has been described, variations of thisconfiguration as well as addition of other components may also be usedand are intended to be covered by this disclosure. For example,collection optics and lenses may be used with this configuration, andvarious modulation techniques may also be used to increase the signal tonoise ratio.

In yet another example of multi-beam detection systems, a dual-beamset-up 4900 such as in FIG. 49 may be used to subtract out (or at leastminimize the adverse effects of) light source fluctuations. In oneembodiment, the output from an SC source 4901 may be collimated using acalcium fluoride (CaF2) lens 4902 and then focused into the entranceslit of the monochromator 4903. At the exit slit, light at the selectedwavelength is collimated again and may be passed through a polarizer4904 before being incident on a calcium fluoride beam splitter 4905.After passing through the beam splitter 4905, the light is split into asample 4906 and reference 4907 arm to enable ratiometric detection thatmay cancel out effects of intensity fluctuations in the SC source 4901.The light in the sample arm 4906 passes through the sample of interestand is then focused onto a HgCdTe detector 4908 connected to a pre-amp.A chopper 4902 and lock-in amplifier 4910 setup enable low noisedetection of the sample arm signal. The light in the reference arm 4907passes through an empty container (cuvette, gas cell etc.) of the samekind as used in the sample arm. A substantially identical detector 4909,pre-amp and lock-in amplifier 4910 is used for detection of thereference arm signal. The signal may then be analyzed using a computersystem 4911. This is one particular example of a method to removefluctuations from the light source, but other components may be addedand other configurations may be used, and these are also intended to becovered by this disclosure.

Although particular examples of detection systems have been described,combinations of these systems or other systems may also be used, andthese are also within the scope of this disclosure. As one example,environmental fluctuations (such as turbulence or winds) may lead tofluctuations in the beam for active remote sensing or hyper-spectralimaging. A configuration such as illustrated in the representativeembodiment of FIG. 49 may be able to remove the effect of environmentalfluctuations. Yet another technique may be to “wobble” the light beamafter the light source using a vibrating mirror. The motion may lead tothe beam moving enough to wash out spatial fluctuations within the beamwaist at the sample or detection system. If the vibrating mirror isscanned faster than the integration time of the detectors, then thespatial fluctuations in the beam may be integrated out. Alternately,some sort of synchronous detection system may be used, where thedetection is synchronized to the vibrating frequency.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for active remote sensing or hyper-spectralimaging. However, many other spectroscopy and identification procedurescan use the near-infrared or SWIR light consistent with this disclosureand are intended to be covered by the disclosure. As one example, thefiber-based super-continuum lasers may have a pulsed output with pulsedurations of approximately 0.5-2 nsec and pulse repetition rates ofseveral Megahertz. Therefore, the active remote sensing orhyper-spectral imaging applications may also be combined with LIDAR-typeapplications. Namely, the distance or time axis can be added to theinformation based on time-of-flight measurements. For this type ofinformation to be used, the detection system would also have to betime-gated to be able to measure the time difference between the pulsessent and the pulses received. By calculating the round-trip time for thesignal, the distance of the object may be judged. In another embodiment,GPS (global positioning system) information may be added, so the activeremote sensing or hyper-spectral imagery would also have a location tagon the data. Moreover, the active remote sensing or hyper-spectralimaging information could also be combined with two-dimensional orthree-dimensional images to provide a physical picture as well as achemical composition identification of the materials. These are justsome modifications of the active remote sensing or hyper-spectralimaging system described in this disclosure, but other techniques mayalso be added or combinations of these techniques may be added, andthese are also intended to be covered by this disclosure.

Section 4: Short-Wave Infrared Super-Continuum Lasers for DetectingCounterfeit or Illicit Drugs and Pharmaceutical Process Control

One advantage of optical systems is that they can perform non-contact,stand-off or remote sensing distance spectroscopy of various materials.As an example, optical systems can be used for identification ofcounterfeit drugs, detection of illicit drugs, or process control in thepharmaceutical industry, especially when the sensing is to be done atremote or stand-off distances in a non-contact, rapid manner. Ingeneral, the near-infrared region of the electromagnetic spectrum coversbetween approximately 0.7 microns (700 nm) to about 2.5 microns (2500nm). However, it may also be advantageous to use just the short-waveinfrared (SWIR) between approximately 1.4 microns (1400 nm) and about2.5 microns (2500 nm). One reason for preferring the SWIR over theentire NIR may be to operate in the so-called “eye safe” window, whichcorresponds to wavelengths longer than about 1400 nm. Therefore, for theremainder of the disclosure the SWIR will be used for illustrativepurposes. However, it should be clear that the discussion that followscould also apply to using the near infrared—NIR—wavelength range, orother wavelength bands.

In particular, wavelengths in the eye safe window may not transmit downto the retina of the eye, and therefore, these wavelengths may be lesslikely to create permanent eye damage from inadvertent exposure. Thenear-infrared wavelengths have the potential to be dangerous, becausethe eye cannot see the wavelengths (as it can in the visible), yet theycan penetrate and cause damage to the eye. Even if a practitioner is notlooking directly at the laser beam, the practitioner's eyes may receivestray light from a reflection or scattering some surface. Hence, it canalways be a good practice to use eye protection when working aroundlasers. Since wavelengths longer than about 1400 nm are substantiallynot transmitted to the retina or substantially absorbed in the retina,this wavelength range is known as the eye safe window. For wavelengthslonger than 1400 nm, in general only the cornea of the eye may receiveor absorb the light radiation.

The SWIR wavelength range may be particularly valuable for identifyingmaterials based on their chemical composition because the wavelengthrange comprises overtones and combination bands for numerous chemicalbonds. For example, in the SWIR numerous hydro-carbon chemical compoundshave overtone and combinational bands, along with oxygen-hydrogen andcarbon-oxygen compounds. Thus, gases, liquids and solids that comprisethese chemical compounds may exhibit spectral features in the SWIRwavelength range. In a particular embodiment, the spectra of organiccompounds may be dominated by the C—H stretch. The C—H stretchfundamental occurs near 3.4 microns, the first overtone is near 1.7microns, and a combination band occurs near 2.3 microns.

One embodiment of remote sensing that is used to identify and classifyvarious materials is so-called “hyper-spectral imaging.” Hyper-spectralsensors may collect information as a set of images, where each imagerepresents a range of wavelengths over a spectral band. Hyper-spectralimaging may deal with imaging narrow spectral bands over anapproximately continuous spectral range. As an example, inhyper-spectral imaging a lamp may be used as the light source. However,the incoherent light from a lamp may spatially diffract rapidly, therebymaking it difficult to perform spectroscopy at stand-off distances orremote distances. Therefore, it would be advantageous to have abroadband light source covering the SWIR that may be used in place of alamp to identify or classify materials in remote sensing or stand-offdetection applications.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. As used throughout this disclosure, the term “spectroscopy”means that a tissue or sample is inspected by comparing differentfeatures, such as wavelength (or frequency), spatial location,transmission, absorption, reflectivity, scattering, fluorescence,refractive index, or opacity. In one embodiment, “spectroscopy” may meanthat the wavelength of the light source is varied, and the transmission,absorption, fluorescence, or reflectivity of the tissue or sample ismeasured as a function of wavelength. In another embodiment,“spectroscopy” may mean that the wavelength dependence of thetransmission, absorption, fluorescence or reflectivity is comparedbetween different spatial locations on a tissue or sample. As anillustration, the “spectroscopy” may be performed by varying thewavelength of the light source, or by using a broadband light source andanalyzing the signal using a spectrometer, wavemeter, or opticalspectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium. In anotherembodiment, the mid-infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium and/orthulium. In one embodiment, the “pump laser” may be a fiber laser, asolid state laser, a laser involving a nonlinear crystal, an opticalparametric oscillator, a semiconductor laser, or a plurality ofsemiconductor lasers that may be multiplexed together. In anotherembodiment, the “pump laser” may be coupled to the gain medium by usinga fiber coupler, a dichroic mirror, a multiplexer, a wavelength divisionmultiplexer, a grating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth of at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, parametricamplification, the Raman effect, modulational instability, andself-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

As used throughout this disclosure, the term “remote sensing” mayinclude the measuring of properties of an object from a distance,without physically sampling the object, for example by detection of theinteractions of the object with an electromagnetic field. In oneembodiment, the electromagnetic field may be in the optical wavelengthrange, including the infrared or SWIR. One particular form of remotesensing may be stand-off detection, which may range exemplary fromnon-contact up to hundreds of meters away.

Identification of Counterfeit Drugs

Pharmaceutical counterfeiting is a growing and significant issue for thehealthcare community as well as the pharmaceutical industry worldwide.As a result of counterfeiting, users may be threatened by substandarddrug quality or harmful ingredients, and legitimate companies may losesignificant revenues. The definition for “counterfeit drug” by the WorldHealth Organization was as follows: “A counterfeit medicine is one whichis deliberately and fraudulently mislabeled with respect to identityand/or source. Counterfeiting can apply to both branded and genericproducts and counterfeit products may include products with the correctingredients or with the wrong ingredients, without active ingredients,with insufficient active ingredient or with fake packaging.” Later thisdefinition was slightly modified, “Counterfeiting in relation tomedicinal products means the deliberate and fraudulent mislabeling withrespect to the identity, composition and/or source of a finishedmedicinal product, or ingredient for the preparation of a medicinalproduct.”

A rapid screening technique such as near-infrared or SWIR spectroscopycould aid in the search for and identification of counterfeit drugs. Inparticular, using a non-lamp based light source could lead tocontact-free control and analysis of drugs. In a particular embodiment,remote sensing, stand-off detection, or hyper-spectral imaging may beused for process control or counterfeit drug identification in a factoryor manufacturing setting, or in a retail, wholesale, or warehousesetting. In one embodiment, the light source for remote sensing maydirect the light beam toward the region of interest (e.g., conveyorbelt, stocking shelves, boxes or cartons, etc), and the diffusereflected light may then be measured using a detection system. Variouskinds of SWIR light sources will be discussed later in this disclosure.The detection system may comprise, in one embodiment, a spectrometerfollowed by one or more detectors. In another embodiment, the detectionsystem may be a dispersive element (examples include prisms, gratings,or other wavelength separators) followed by one or more detectors ordetector arrays. In yet another embodiment, the detection system maycomprise a Fourier transform infrared spectrometer. These are merelyspecific examples of the detection system, but combinations of these orother detection systems may also be used and are contemplated within thescope of this disclosure.

For monitoring drugs, the SWIR light source and the detection systemcould be used in transmission, reflection, fluorescence, or diffusereflection. Also, different system configurations may also be used andare included in the scope of this disclosure. For example, the lightsource and detection system may be placed in a fixed location, and forreflection the light source and detectors may be close to one another,while for transmission the light source and detectors may be atdifferent locations. The region of interest may be surveyed, and thelight beam may also be scanned to cover an area larger than the lightsource beam. In yet another embodiment, the system could be placed on avehicle such as an automobile or a truck, or the light source could beplaced on one vehicle, while the detection system is on another vehicle.If the light source and detection system are compact and lightweight,they might even be carried by a person in the field, either in theirhands or in a backpack.

Another advantage of using the near-infrared or SWIR is that most drugpackaging materials are at least partially transparent in thiswavelength range, so that drug compositions may be detected andidentified through the packaging non-destructively. As an example, SWIRlight could be used to see through plastics, since the signature forplastics can be subtracted off and there are large wavelength windowswhere the plastics are transparent. FIG. 50 illustrates the absorbance5000 for two common plastics: polyethylene 5001 and polystyrene 5002.Because of the hydro-carbon bonds, there are absorption features near1.7 microns and 2.2-2.5 microns. In general, the absorption bands in thenear infrared are due to overtones and combination bands for variousfunctional group vibrations, including signals from C—H, O—H, C═O, N—H,—COOH, and aromatic C—H groups. It may be difficult to assign anabsorption band to a specific functional group due to overlapping ofseveral combinations and overtones. However, with advancements incomputational power and chemometrics or multivariate analysis methods,complex systems may be better analyzed. In one embodiment, usingsoftware analysis tools the absorption spectrum may be converted to itssecond derivative equivalent. The spectral differences may permit afast, accurate, non-destructive and reliable identification ofmaterials. Although particular derivatives are discussed, othermathematical manipulations may be used in the analysis, and these othertechniques are also intended to be covered by this disclosure.

Spectroscopy in the near-infrared or SWIR may be sensitive to both thechemical and physical nature of the sample composition and may beperformed rapidly with minimal sample preparation. For example,near-infrared or SWIR spectroscopy may be used to study the homogeneityof powder samples, particle size determinations, product composition,the determination of the concentrations and distribution of componentsin solid tablets and content uniformity, among other applications. Inyet other embodiments, applications include tablet identification,determination of moisture, residual solvents, active ingredient potency,the study of blending operations, and the detection of capsuletampering.

FIG. 51 illustrates one example of the difference in near-infraredspectrum 5100 between an authentic tablet and a counterfeit tablet. Twogrades of film coated tablets comprising drugs were investigated: curve5101 is the genuine drug, while 5102 is a counterfeit drug. These twogrades of capsules have noticeably different contents, and thedifferences are apparent in the near-infrared or SWIR spectra. In somecases the differences may not be as distinct. For these cases, moresignal processing may be necessary to distinguish between samples.

In another embodiment, it may be advantageous to take a first, second orhigher order derivative to elucidate the difference between real andcounterfeit drugs. For example, FIG. 52 shows the second derivative 5200of the spectral comparison of Prozac 5201 and a similarly formulatedgeneric 5202, which had a fluoxetine hydrochloride (10 mg). Although thereflectance curves from the two samples are close and, therefore,difficult to distinguish, the second derivative of the data helps tobring out the differences more clearly. Although a second derivative isused in this example, any number of signal processing algorithms andmethods may be used, and these are also intended to be covered by thisdisclosure. For example, partial least square algorithms, multivariatedata analysis, principal component analysis, or chemometric software maybe implemented without departing from the scope of this disclosure.

In yet another embodiment, near-infrared or SWIR spectroscopy may beused to measure and calibrate various pharmaceutical formulations basedon the active pharmaceutical ingredients and excipients. An excipientmay be a pharmacologically inactive substance used as a carrier for theactive ingredients of a medication. In some cases, the active substancemay not be easily administered and/or absorbed by the human body; insuch cases the active ingredient may be dissolved into or mixed with anexcipient. Also, excipients are also sometimes used to bulk upformulations that contain very potent active ingredients, to allow forconvenient and accurate dosage. In addition to their use in thesingle-dosage quantity, excipients can be used in the manufacturingprocess to aid in the handling of the active substance concerned.

FIG. 53 shows an example of the near-infrared spectra 5300 for differentpure components of a studied drug. The spectrum for the activepharmaceutical ingredient (API) 5301 is plotted, along with the spectrafor five different excipients 5302, 5303, 5304, 5305 and 5306. Eachspectrum has been baseline shifted to avoid overlapping. Thenear-infrared spectra have been obtained by averaging the spectra ofeach pixel of an area of a hyper-spectral image. As FIG. 53 shows, eachof the chemical compositions have a distinct spectrum, and thecomposition of a drug may be decomposed into its constitutiveingredients. These are just some examples of how near-infrared or SWIRspectroscopy may be applied to counterfeit drug detection, but othermethods and analysis techniques may also be used without departing fromthe scope of this disclosure. As one other example, once the activepharmaceutical ingredient and the excipients spectral distribution of adrug formulation are understood, feedback may be provided of thisinformation to the drug development stages.

Rapid Screening for Illicit Drugs

Thus, FIGS. 51-53 show that near-infrared or SWIR spectroscopy may beused to identify counterfeit drugs. More generally, various materialsincluding illicit drugs, explosives, fertilizers, vegetation, and paintshave features in the near-infrared and SWIR that can be used to identifythe various samples, and these applications are also intended to bewithin the scope of this disclosure. Although stronger features may befound in the mid-infrared, the near-infrared may be easier to measuredue to higher quality detection systems, more mature fiber optics andlight sources, and transmission through atmospheric transmissionwindows. Because of these distinct spectral signatures, these materialscould also be detected using active remote sensing, hyper-spectralimaging, or near-infrared or SWIR spectroscopy. As just another example,illicit drugs may be detectable using remote sensing, hyper-spectralimaging, or near-infrared spectroscopy. FIG. 54 shows the mid-waveinfrared and long-wave infrared absorption spectra 5400 for variousillicit drugs. The absorbance for cocaine 5401, methamphetamine 5402,MDMA (ecstasy) 5403, and heroin 5404 are plotted versus wavelength fromapproximately 2.5-20 microns. Although the fundamental resonances forthese drugs may lie in the longer wavelength regions, there arecorresponding overtones and combination bands in the SWIR andnear-infrared wavelength range. Therefore, the active remote sensing,hyper-spectral imaging, or near-infrared or SWIR spectroscopy techniquesdescribed herein may also be applicable to detecting illicit drugs fromaircraft, vehicles, or hand held devices.

The diffuse reflectance technique may be useful with near-infrared orSWIR spectroscopy for rapid identification of illegal drugs due tosimple handling and simple use of a search data library created usingnear-infrared diffuse reflectance. For instance, FIG. 55 illustrates theabsorbance 5500 versus wavelength in the near-infrared region for fourclasses of illegal drugs. In particular, the spectra are shown formethamphetamine (MA) 5501, amphetamine (AP) 5502, MDMA (street name:ecstasy) 5503, and MDA (street name: the love drug) 5504. Each of theillegal drugs have unique spectral features in the near-infrared andSWIR. Also, comparing the mid-infrared spectrum for MDMA (5403 in FIG.54) with the near-infrared spectrum for MDMA (5503 in FIG. 55), it seemsclear that the near-infrared region shows overtones and combinationbands that should be discernible. Referring to FIG. 55, sampleidentification may be accomplished by using the region (indicated by thearrows) where the spectral absorptions may provide specific peaksdepending on the drug component.

In another embodiment, FIG. 56 shows the diffuse reflectancenear-infrared spectrum 5600 of heroin samples. Heroin, the 3,6-diacetylderivative of morphine (hence diacetyl-morphine) is an opiate drugsynthesized from morphine, which is usually a naturally occurringsubstance extracted from the seedpod of certain varieties of poppyplants. In particular, 5601 is the near-infrared spectrum for an illicitstreet drug sample, while 5602 is the spectra for a pure heroinstandard. The difference between the spectra may arise at least in partfrom cutting agents. The inset 5603 shows the molecular structure forheroin. As in the other examples, the absorption in the near-infraredrange is caused by overtone and combination vibrations of O—H, C—H, N—Hand C═O groups, which exhibit their fundamental molecular stretching andbending absorption in the mid-infrared range (c.f., the mid-infraredspectrum for heroin is shown 5404 in FIG. 54). These overtone andcombination bands do not behave in a simple way, making thenear-infrared spectra complex and harder to directly interpret. Also,although the near-infrared signatures may be weaker in magnitude, theyare probably easier to detect in the near-infrared, and the samplepreparation may also be much simpler in the near-infrared. Moreover, forremote sensing, the near-infrared may be preferable because ofatmospheric transmission windows between approximately 1.4-1.8 micronsand 2-2.5 microns.

Pure heroin may be a white powder with a bitter taste that is rarelysold on the streets, while illicit heroin may be a powder varying incolor from white to dark brown due to impurities left from themanufacturing process or the presence of additives. The purity of streetheroin may also vary widely, as the drug can be mixed with other whitepowders. The impurity of the drug may often make it difficult to gaugethe strength of the dosage, which runs the risk of overdose. One nicefeature of near-infrared or SWIR spectroscopy is that the technique maybe used in a non-destructive, non-contact manner to determine rapidlythe concentration of compounds present in complex samples at percentagelevels with very little sample preparation. In a particular embodiment,FIG. 57 illustrates the diffuse reflectance near-infrared spectra 5700of different seized illicit drugs containing heroin (between 10.7 and21.8%) compared with the spectrum of pure heroin 5701. Curve 5702 is for21.8% by weight, curve 5703 is 13.2% by weight, curve 5704 is 17% byweight, and curve 5705 is 10.7% by weight of heroin. The spectra havebeen shifted along the vertical axis to better illustrate thedifferences.

Although quite complex in the near-infrared, it may be possible toidentify from the pure heroin near-infrared spectrum (5701 in FIG. 57 or5602 in FIG. 56) the main wavelengths related to the most commonfunctional groups in heroin. For example, FIG. 58 lists possible bandassignments 5800 for the various spectral features in pure heroin. Ascan be seen from FIG. 58, the absorption in the near-infrared may bemainly due to overtone and combination bands associated with O—H, C—H,N—H and C═O groups.

As can be appreciated from FIG. 57, there may be significant differencesbetween the spectrum of pure heroin and sample spectra. Thesedifferences may be due to the presence of different compounds used ascutting agents, which can affect the shape and intensity of thenear-infrared signals. FIG. 59 illustrates the diffuse reflectancenear-infrared spectra 5900 of different compounds that may be frequentlyemployed as cutting agents. In the bottom of FIG. 59 are shown thespectra 5908 for pure heroin and the spectra 5907 for a seized illicitstreet drug sample comprising 21.8% of heroin. The spectra for variouscutting agents include: 5901 for flour, 5902 for talcum powder, 5903 forchalk, 5904 for acetylsalicylic acid, 5905 for caffeine, and 5906 forparacetamol. Thus, near-infrared or SWIR spectroscopy may be used towork back to the composition of an unknown drug. Although particularexamples of counterfeit and illicit drugs have been described, thenear-infrared or SWIR spectroscopy (including diffuse reflectance,reflectance, flourescence or transmission) may also be applied to theidentification of other drugs and substances without departing from thescope of this disclosure. This spectroscopy may be usednon-destructively and non-contact over stand-off distances or in remotesensing distances, whether from an airborne, vehicle, hand-held, orstationary platform.

Process Analytical Technology (PAT)

One definition of process analytical technology, PAT, is “a system fordesigning, analyzing and controlling manufacturing through timelyevaluations (i.e., during processing) of significant quality andperformance attributes of raw and in-process materials and processes,with the goal of ensuring final product quality.” Near-infrared or SWIRspectroscopy may have applications in the PAT of the pharmaceuticalindustry by providing, for example, quantitative analysis of multiplecomponents in a sample and in pack quantification of drugs informulation, as well as quality of a drug and quality control of complexexcipients used in formulation. The PAT process may benefit fromnear-infrared or SWIR spectroscopy for some steps, such as: raw materialidentification, active pharmaceutical ingredient applications, drying,granulation, blend uniformity and content uniformity. Some of thestrengths of near-infrared or SWIR spectroscopy include: radiation hasgood penetration properties, and, thus, minimal sample preparation maybe required; measurement results may be obtained rapidly, andsimultaneous measurements may be obtained for several parameters;non-destructive methods with little or no chemical waste; and organicchemicals that comprise most pharmaceutical products have unique spectrain the near-infrared and SWIR ranges, for example.

FIG. 60 shows one example of a flow-chart 6000 in the PAT for thepharmaceutical industry. While the center shows the steps of themanufacturing process 6001, the top and bottom sides show wherenear-infrared spectroscopy could be applicable for lab use 6002 (top) orin process monitoring control 6003 (bottom). Indeed, near-infrared orSWIR spectroscopy has the potential to benefit almost every step in themanufacturing process. Just to provide a few examples of usingnear-infrared or SWIR spectroscopy in the PAT process, the raw materialtesting and blending process will be examined briefly.

At the commencement of manufacture of a drug product, it may be requiredto identify the correct material and grade of the pharmaceuticalexcipients to be used in the formulation. FIG. 61 illustrates thetypical near-infrared spectra 6100 for a variety of excipients. Includedin the graph 6100 are spectra for: magnesium stearate 6101, sorbitol6102, mannitol 6103, talc 6104, lactose 6105, starch 6106, maltodextrin6107, and microcrystalline cellulose 6108. A suitable spectral databasemay be used to rapidly identify and qualify excipients. One nice aspectof the spectroscopy is that the near-infrared and SWIR are sensitive toboth the physical and chemical characteristics of the samples.

One of the next steps in the manufacture of a dosage form is theblending together of the active component with the excipients to producea homogeneous blend. In one embodiment, the near-infrared or SWIRspectroscopy apparatus may comprise a fiber-optic probe, which may, forexample, interface with the blending vessel. For such a fiber-opticprobe, near infrared or SWIR spectra may be collected in real-time froma blending process. FIG. 62 exemplifies the absorbance 6200 from theblending process. Although the initial spectra 6201 shows differencesfrom the eventual spectra, as the process continues the blend convergesto the final spectra 6202 and continues to overlap that spectra. Similarconverging or overlapping spectra may also be used to check the productuniformity at the end of the process. The near-infrared spectra may beacquired in real-time; and, using appropriate data pre-processing andchemometric analysis, blend homogeneity plots may be derived, such as6200.

One goal of the manufacturing process and PAT may be the concept of a“smart” manufacturing process, which may be a system or manufacturingoperation responding to analytical data generated in real-time. Such asystem may also have an in-built “artificial intelligence” as decisionsmay be made whether to continue a manufacturing operation. For example,with respect to the raw materials, integration of the qualitymeasurement into smart manufacturing processes could be used to improvemanufacturing operations by ensuring that the correct materials of theappropriate quality are used in the manufacture. Similarly, a smartblender would be under software control and would respond to thereal-time spectral data collected.

FIG. 63 illustrates what might be an eventual flow-chart 6300 of a smartmanufacturing process. The manufacturing process 6301 may have as inputthe process feed 6302 and result in a process output 6303. A processcontroller 6304 may at least partially control the manufacturing process6301, and the controller 6304 may receive inputs from the closed loopcontrol (process parameters) 6305 as well as the on-line monitoring ofprocess parameters 6306. The feedback loops in the process could refinethe manufacturing process 6301 and improve the quality of the processoutput 6303. These are particular embodiments of the use ofnear-infrared or SWIR spectroscopy in the PAT of the pharmaceuticalindustry, but other variations, combinations, and methods may also beused and are intended to be covered by this disclosure.

The discussion thus far has centered on use of near-infrared or SWIRspectroscopy in applications such as identification of counterfeitdrugs, detection of illicit drugs, and pharmaceutical process control.Although drugs and pharmaceuticals are one example, many other fieldsand applications may also benefit from the use of near infrared or SWIRspectroscopy, and these may also be implemented without departing fromthe scope of this disclosure. As just another example, near-infrared orSWIR spectroscopy may also be used as an analytic tool for food qualityand safety control. Applications in food safety and quality assessmentinclude contaminant detection, defect identification, constituentanalysis, and quality evaluation. The techniques described in thisdisclosure are particularly valuable when non-destructive testing isdesired at stand-off or remote distances.

In one example, near-infrared or SWIR spectroscopy may be used in cerealbreeding. The breeding purposes may require knowledge on bothcomposition and functional properties of grain, while the functionalityof wheat grain is an issue for wheat breeders. Most of the wheatfunctionality parameters depend on the protein-proteinase complex ofwheat grain, as well as the condition of the carbohydrate complex. FIG.64A illustrates the near-infrared reflectance spectrum 6400 of wheatflour. Since these samples are complex in composition, several organicbonds involving hydrogen vibrate to produce overlapped spectral bands.Thus, the resulting spectrum 6400 appears like a wavy line withoutclearly defined features. Analytical methods based on this type ofspectroscopy may have the potential to improve the quality of finalcereal products by testing the products through the entire productionprocess in the processing industry.

In yet another embodiment, near-infrared or SWIR spectroscopy may beused for the assessment of fruit and vegetable quality. Most commercialquality classification systems for fruit and vegetables are based onexternal features of the product, such as shape, color, size, weight andblemishes. However, the external appearance of most fruit is generallynot an accurate guide to the internal eating quality of the fruit. As anexample, for avocado fruit the external color is not a maturitycharacteristic, and its smell is too weak and appears later in itsmaturity stage. Analysis of the near-infrared or SWIR absorption spectramay provide qualitative and quantitative determination of manyconstituents and properties of horticulture produce, including oil,water, protein, pH, acidity, firmness, and soluble solids content ortotal soluble solids of fresh fruits. FIG. 64B shows the near-infraredabsorbance spectra 6450 obtained in diffusion reflectance mode for aseries of whole ‘Hass’ avocado fruit. Four oil absorption bands are near2200-2400 nm (CH2 stretch bend and combinations), with weaker absorptionaround 750 nm, 1200 nm, and 900-930 nm ranges. On the other hand, near1300-1750 nm range may be useful for determining the protein and oilcontent. The 900-920 nm absorbance band may be useful for sugardetermination. Although described in the context of grains, fruits, andvegetables, the near-infrared or SWIR spectroscopy may also be valuablefor other food quality control and assessment, such as measuring theproperties of meats. These and other applications also fall within thescope of this disclosure.

Detection Systems

The near-infrared or SWIR spectroscopy system, remote sensing system orhyper-spectral imaging system may be on an airborne platform, mounted ona vehicle, a stationary transmission or reflection set-up, or even heldby a human for a compact system. For such a system, there arefundamentally two hardware parts: the transmitter or light source andthe detection system. Between the two, perhaps in a transmission orreflection setting, may be the sample being tested or measured.Moreover, the output from the detection system may go to a computationalsystem, comprising computers or other processing equipment. The outputfrom the computational system may be displayed graphically as well aswith numerical tables and perhaps an identification of the materialcomposition. These are just some of the parts of the systems, but otherelements may be added or be eliminated, and these modifiedconfigurations are also intended to be covered by this disclosure.

By use of an active illuminator, a number of advantages may be achieved.First, stand-off or remote distances may be achieved if a non-lampsystem is used—i.e., if the beam does not rapidly diffract. Also, highersignal-to-noise ratios may be achieved. For example, one way to improvethe signal-to-noise ratio would be to use modulation and lock-intechniques. In one embodiment, the light source may be modulated, andthen the detection system would be synchronized with the light source.In a particular embodiment, the techniques from lock-in detection may beused, where narrow band filtering around the modulation frequency may beused to reject noise outside the modulation frequency. In anotherembodiment, change detection schemes may be used, where the detectionsystem captures the signal with the light source on and with the lightsource off. Again, for this system the light source may be modulated.Then, the signal with and without the light source is differenced.Change detection may help to identify objects that change in the fieldof view. In the following some exemplary detection systems aredescribed.

In one embodiment, a SWIR camera or infrared camera system may be usedto capture the images. The camera may include one or more lenses on theinput, which may be adjustable. The focal plane assemblies may be madefrom mercury cadmium telluride material (HgCdTe), and the detectors mayalso include thermo-electric coolers. Alternately, the image sensors maybe made from indium gallium arsenide (InGaAs), and CMOS transistors maybe connected to each pixel of the InGaAs photodiode array. The cameramay interface wirelessly or with a cable (e.g., USB, Ethernet cable, orfiber optics cable) to a computer or tablet or smart phone, where theimages may be captured and processed. These are a few examples ofinfrared cameras, but other SWIR or infrared cameras may be used and areintended to be covered by this disclosure.

In another embodiment, an imaging spectrometer may be used to detect thelight received from the sample. For example, FIG. 65A shows a schematicdiagram 6500 of the basic elements of an imaging spectrometer. The inputlight 6501 from the sample may first be directed by a scanning mirrorand/or other optics 6502. An optical dispersing element 6503, such as agrating or prism, in the spectrometer may split the light into manynarrow, adjacent wavelength bands, which may then be passed throughimaging optics 6504 onto one or more detectors or detector arrays 6505.Some sensors may use multiple detector arrays to measure hundreds ofnarrow wavelength bands.

An example of a typical imaging spectrometer 6550 used in hyper-spectralimaging systems is illustrated in FIG. 65B. In this particularembodiment, the input light may be directed first by a tunable mirror6551. A front lens 6552 may be placed before the entrance slit 6553 andthe collector lens 6554. In this embodiment, the dispersing element is aholographic grating with a prism 6555, which separates the differentwavelength bands. Then, a camera lens 6556 may be used to image thewavelengths onto a detector or camera 6557.

FIG. 65 provide particular examples, but some of the elements may not beused, or other elements may be added, and these are also intended to becovered by this disclosure. For instance, a scanning spectrometer may beused before the detector, where a grating or dispersive element isscanned to vary the wavelength being measured by the detector. In yetanother embodiment, filters may be used before one or more detectors toselect the wavelengths or wavelength bands to be measured. This may beparticularly useful if only a few bands or wavelengths are to bemeasured. The filters may be dielectric filters, Fabry-Perot filters,absorption or reflection filters, fiber gratings, or any otherwavelength selective filter. In one embodiment, a wavelength divisionmultiplexer, WDM, may be used followed by one or more detectors ordetector arrays. One example of a planar wavelength division multiplexermay be a waveguide grating router or an arrayed waveguide grating. TheWDM may be fiber coupled, and detectors may be placed directly at theoutput or the detectors may be coupled through fibers to the WDM. Someof these components may also be combined with the configurations in FIG.65.

While the above detection systems could be categorized as single pathdetection systems, it may be advantageous in some cases to usemulti-path detection systems. In one embodiment, a detection system froma Fourier transform infrared spectrometer, FTIR, may be used. Thereceived light may be incident on a particular configuration of mirrors,called a Michelson interferometer, that allows some wavelengths to passthrough but blocks others due to wave interference. The beam may bemodified for each new data point by moving one of the mirrors, whichchanges the set of wavelengths that pass through. This collected data iscalled an interferogram. The interferogram is then processed, typicallyon a computing system, using an algorithm called the Fourier transform.One advantageous feature of FTIR is that it may simultaneously collectspectral data in a wide spectral range.

FIG. 66 illustrates one example of the FTIR spectrometer 6600. Lightfrom the near-infrared or SWIR light source 6601 may be collimated anddirected to a beam splitter 6602. In one embodiment, the beam splitter6602 may be a 50:50 beam splitter. One portion of the beam 6603 may bereflected toward a stationary mirror 6604, while the other portion ofthe beam 6605 may be transmitted towards a moving mirror 6606. Light maybe reflected from the two mirrors 6604, 6606 back to the beam splitter6602, and then a portion of the recombined beam 6607 may be directedtoward the sample 6608. The recombined beam 6607 may be focused onto thesample 6608, in one embodiment. On leaving the sample 6608, the lightmay be refocused or at least collected at a detector 6609. A backgroundinterferogram may be obtained by using the set-up 6600 without a samplein the chamber 6608. When a sample is inserted into 6608, the backgroundinterferogram may be modulated by the presence of absorption bands inthe sample. The FTIR spectrometer may have several advantages comparedto a scanning (dispersive) spectrometer. Since all the wavelengths maybe collected simultaneously, the FTIR may result in a highersignal-to-noise ratio for a given scan time or a shorter scan time for agiven resolution. Moreover, unlike a spectrometer where a slit may limitthe amount of the beam detected, the FTIR may accommodate the entirediameter of the beam coming from the light source 6601. Theconfiguration 6600 is one example of an FTIR, but other configurationsmay also be used, and these are also intended to be covered by thisdisclosure.

In yet another example of multi-beam detection systems, a dual-beamset-up 6700 such as in FIG. 67 may be used to subtract out (or at leastminimize the adverse effects of) light source fluctuations. In oneembodiment, the output from an SC source 6701 may be collimated using aCaF2 lens 6702 and then focused into the entrance slit of themonochromator 6703. At the exit slit, light at the selected wavelengthis collimated again and may be passed through a polarizer 6704 beforebeing incident on a calcium fluoride beam splitter 6705. After passingthrough the beam splitter 6705, the light is split into a sample 6706and reference 6707 arm to enable ratiometric detection that may cancelout effects of intensity fluctuations in the SC source 6701. The lightin the sample arm 6706 passes through the sample of interest and is thenfocused onto a HgCdTe detector 6708 connected to a pre-amp. A chopper6702 and lock-in amplifier 6710 setup enable low noise detection of thesample arm signal. The light in the reference arm 6707 passes through anempty container (cuvette, gas cell etc.) of the same kind as used in thesample arm. A substantially identical detector 6709, pre-amp and lock-inamplifier 6710 is used for detection of the reference arm signal. Thesignal may then be analyzed using a computer system 6711. This is oneparticular example of a method to remove fluctuations from the lightsource, but other components may be added and other configurations maybe used, and these are also intended to be covered by this disclosure.

Although particular examples of detection systems have been described,combinations of these systems or other systems may also be used, andthese are also within the scope of this disclosure. As one example,environmental fluctuations (such as turbulence or winds) may lead tofluctuations in the beam for active remote sensing or hyper-spectralimaging. A configuration such as FIG. 67 may be able to remove theeffect of environmental fluctuations. Yet another technique may be to“wobble” the light beam after the light source using a vibrating mirror.The motion may lead to the beam moving enough to wash out spatialfluctuations within the beam waist at the sample or detection system. Ifthe vibrating mirror is scanned faster than the integration time of thedetectors, then the spatial fluctuations in the beam may be integratedout. Alternately, some sort of synchronous detection system may be used,where the detection is synchronized to the vibrating frequency.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for spectroscopy, active remote sensing orhyper-spectral imaging. However, many other spectroscopy andidentification procedures can use the near-infrared or SWIR lightconsistent with this disclosure and are intended to be covered by thedisclosure. As one example, the fiber-based super-continuum lasers mayhave a pulsed output with pulse durations of approximately 0.5-2 nsecand pulse repetition rates of several Megahertz. Therefore, thenear-infrared or SWIR spectroscopy, active remote sensing orhyper-spectral imaging applications may also be combined with LIDAR-typeapplications. Namely, the distance or time axis can be added to theinformation based on time-of-flight measurements. For this type ofinformation to be used, the detection system would also have to betime-gated to be able to measure the time difference between the pulsessent and the pulses received. By calculating the round-trip time for thesignal, the distance of the object may be judged. In another embodiment,GPS (global positioning system) information may be added, so thenear-infrared or SWIR spectroscopy, active remote sensing orhyper-spectral imagery would also have a location tag on the data.Moreover, the near-infrared or SWIR spectroscopy, active remote sensingor hyper-spectral imaging information could also be combined withtwo-dimensional or three-dimensional images to provide a physicalpicture as well as a chemical composition identification of thematerials. These are just some modifications of the near-infrared orSWIR spectroscopy, active remote sensing or hyper-spectral imagingsystem described in this disclosure, but other techniques may also beadded or combinations of these techniques may be added, and these arealso intended to be covered by this disclosure.

Section 5: Near-Infrared Super-Continuum Lasers for Early Detection ofBreast and Other Cancers

To perform non-invasive optical mammography, one desired attribute isthat the light may penetrate as far as possible into the breast tissue.In diffuse reflection spectroscopy, a broadband light spectrum may beemitted into the tissue, and the spectrum of the reflected ortransmitted light may depend on the absorption and scatteringinteractions within the target tissue. Since breast tissue hassignificant water and hemoglobin content, it is valuable to examine thewavelength range over which deep penetration of light is possible. FIG.68 illustrates the optical absorption 6800 of pure water (dotted line)6801, hemoglobin without oxygen (thinner solid line) 6802, andhemoglobin saturated with oxygen (thicker solid line) 6803. It can benoted that above about 1100 nm, the absorption of hemoglobin is almostthe same as water absorption. The penetration depth may be proportionalto the inverse of the optical absorption. Therefore, the highestpenetration depth will be at the absorption valley, approximately in thewavelength range between about 900 nm and about 1300 nm. Although not aslow in absorption compared to the first window, another absorptionvalley lies between about 1600 nm and 1800 nm. Thus, non-invasiveimaging preferably should use wavelengths that fall in one of these twoabsorption valleys.

FIG. 69 shows examples of various absorption bands of chemical species6900 in the wavelength range between about 1200 nm and 2200 nm. Althoughthe fundamental absorptions usually lie in the mid-infrared (e.g.,wavelengths longer than about 3 microns), there are many absorptionlines in the NIR corresponding to the second overtone region 6901between about 1000 nm and 1700 nm, the first overtone region 6902between about 1500 nm and 2050 nm, and the combination band region 6903between about 1900 nm and 2300 nm. As an example, hydrocarbon bondscommon in many biological substances have their fundamental absorptionin the mid-IR near 3300-3600 nm, but they also have many combinationband lines between 2000-2500 nm, and other lines at shorter wavelengthscorresponding to the first and second overtones. Fortunately, there arespectral features of FIG. 69 that overlap with the absorption valleys inFIG. 68. These are likely to be the wavelengths of interest forspectroscopic analysis of cancerous regions.

In women, the breasts (FIG. 70) 7000 overlay the pectoralis majormuscles 7002 and cover much of the chest area and the chest walls 7001.The breast is an apocrine gland that produces milk to feed an infantchild; the nipple 7004 of the breast is surrounded by an areola 7005,which has many sebaceous glands. The basic units of the breast are theterminal duct lobules 7003, which produce the fatty breast milk. Theygive the breast its function as a mammary gland. The lobules 7003 feedthrough the milk ducts 7006, and in turn these ducts drain to the nipple7004. The superficial tissue layer (superficial fascia) may be separatedfrom the skin 7008 by about 0.5-2.5 cm of adipose of fatty tissue 7007.

Breast cancer is a type of cancer originating from breast tissue, mostcommonly from the inner lining of milk ducts 7006, the lobules 7003 thatsupply the ducts with milk, and/or the connective tissue between thelobules. Cancers originating from ducts 7006 are known as ductalcarcinomas, while those originating from lobules 7003 or theirconnective tissue are known as lobular carcinomas. While theoverwhelming majority of human cases occur in women, male breast cancermay also occur.

Several particular embodiments of imaging systems 7100, 7150 foroptically scanning a breast are illustrated in FIG. 71. In theseparticular embodiments, the patient 7101, 7151 may lie in a proneposition with her breasts inside a box 7102, 7152 with probably atransparent window on the detector side. A compression plate 7103, 7153may hold the breast in place against the viewing window by mildlycompressing the breast to a thickness between about 5.5 and 7.5 cm. Thebox 7102, 7152 may then be filled with a matching fluid with opticalproperties similar to human breast. In one instance, the matching fluidmay comprise water, india ink for absorption, and a fat emulsion forscattering. The embodiments in FIG. 71 may also have one or moredetectors 7104, 7155, one or more light sources 7104, 7154, variouselectronics, and even an imaging system based on charge coupled devices7105. As illustrated in FIG. 71, the light sources 7104, 7154 anddetectors 7104, 7155 may be coupled to the box 7102, 7152 through one ormore fibers 7106, 7156. Also, the imaging may be in reflection mode (topof FIG. 71), transmission mode (bottom of FIG. 71), or some combination.

Beyond the geometry and apparatus of FIG. 71, the optical imaging systemmay use one or more of three different illumination methods: continuouswave, time-domain photon migration, and frequency-domain photonmigration. In one embodiment, continuous-wave systems emit light atapproximately constant intensity or modulated at low frequencies, suchas 0.1-100 kHz. In another embodiment, the time-domain photon migrationtechnique uses relatively short, such as 50-400 psec, light pulses toassess the temporal distribution of photons. Since scattering mayincrease the times of flight spent by photons migrating in tissues, thephotons that arrive earliest at the detector probably encountered thefewest scattering events. In yet another embodiment, thefrequency-domain photon migration devices modulate the amplitude of thelight that may be continuously transmitted at relatively highfrequencies, such as 10 MHz to 1 GHz. For example, by measuring thephase shift and amplitude decay of photons as compared to a referencesignal, information may be acquired on the optical properties of tissue,and scattering and absorption may be distinguished. Beyond these threemethods, other techniques or combinations of these methods may be used,and these other methods are also intended to fall within the scope ofthis disclosure.

Although particular embodiments of imaging architectures are illustratedin FIG. 71, other system architectures may also be used and are alsointended to be covered by this disclosure. For example, in oneembodiment several couples of optical fibers for light delivery andcollection may be arranged along one or more rings placed at differentdistances from the nipple 7004. In an alternate embodiment a “cap” withfiber leads for light sources and detectors may be used that fits overthe breast. In yet another embodiment, imaging optics and light sourcesand detectors may surround the nipple 7004 and areola 7005 regions ofthe breast. As yet another alternative, a minimally invasive proceduremay involve inserting needles with fiber enclosure (to light sources anddetectors or receivers) into the breast, so as to probe regions such asthe lobules 7003 and connective tissue. Both non-invasive and minimallyinvasive optical imaging methods are intended to be covered by thisdisclosure.

Optical Wavelength Ranges for Cancer Detection

Many of the diffuse optical tomography studies previously conducted haverelied on using NIR in the wavelength range of about 600-1000 nm, wherelight absorption at these wavelengths may be minimal, allowing forsufficient tissue penetration (up to 15 cm). In these wavelength ranges,it has been claimed that concentrations of oxy- and deoxy-hemoglobin,water, and lipids can be determined. For example, FIG. 72 shows thenormalized absorption spectra 7200 of main tissue absorbers in the NIRbetween about 600 nm and 1100 nm: deoxy-hemoglobin, Hb, 7201,oxy-hemoglobin, HbO2, 7202, water 7203, lipids 7204 and collagen 7205.It is speculated that in a malignant tumor, hemoglobin concentration maybe directly related to angiogenesis, one of the main factors requiredfor tumor growth and metastases. Moreover, the proportions of oxy- anddeoxy-hemoglobin in a tumor may change due to its metabolism. Thus, bymeasuring concentrations of the breast components, discrimination ofbenign and malignant tumors may be possible with diffuse opticalimaging. Experiment evidence suggests that cancerous tissue isassociated with higher hemoglobin and water concentrations, and a lowerlipid concentration with respect to normal breast tissue.

Based on FIG. 68 and the dynamics of carcinoma, it may be advantageousto perform spectroscopy in longer wavelengths, such as windows between1000-1400 nm or 1600-1800 nm. For example, looking at the absorptioncurves 6800 in FIG. 68, the absorption between approximately 1000-1300nm may be comparable to the 600-1000 nm window described in FIG. 72.However, the loss through the soft tissue medium (penetration depth maybe inversely related to the loss) will be due to absorption andscattering. In fact, the scattering properties of tissue may alsocontain valuable information for lesion diagnosis. Since the scatteringis inversely proportional to some power of wavelength (for example, insome tissue scattering is inversely proportional to the wavelengthcubed), the scattering contribution to the loss may decrease at longerwavelengths. Moreover, these longer wavelength windows may containdiagnostic information on content of collagen and adipose, both of whichmay be significant indicators for breast cancer.

Breast cancer spectroscopy may benefit from the use of wavelengthslonger than about 1000 nm for a number of reasons. As one example, themain absorbers in soft tissues of the visible spectrum of light may beoxy- and deoxygenated hemoglobin and beta-carotene. On the other hand,primary absorbers in the near-infrared spectrum of light may be water,adipose tissue and collagen. Particularly adipose and collagen contentmay be valuable for early detection of cancers. In one embodiment,increased levels of collagen in breast malignancies are thought to bedue to increased vascularity of the tumors. Collagen type I may be animportant component of artery walls. FIG. 73 illustrates the normalizedabsorption coefficient 7300 in the wavelength range between about 500 nmand 1600 nm for Hb 7301, HbO2 7302, beta-carotene 7303, water 7304,lipid 7305 and collagen 7306.

Collagen and Adipose Signatures in Near-IR

Examining the collagen content may be a valuable indicator for breastcancer detection. Collagen is one of the important extracellular matrixproteins, and fibrillar collagens help to determine stromalarchitecture. In turn, changes in the stromal architecture andcomposition are one of the aspects of both benign and malignantpathologies, and, therefore, may play an initial role in breastcarcinogenesis. For example, collagen seems to be related to cancerdevelopment, because high mammographic density may be recognized as arisk factor for breast cancer. Moreover, collagen type in high-riskdense breasts may appear to be different from collagen in low-densitybreasts.

Experimental data also shows that malignant mammary gland tissues ofanimals and humans show a decrease in lipids when compared to normaltissues. The reduced amounts of lipids in the cancerous sites may becaused by a high metabolic demand of lipids in the malignant tumors. Forexample, due to the rapid proliferation of cancerous cells, there may bereduced lipid content in cancerous tissues. Thus, in addition tocollagen, another valuable marker for breast cancer may be the lipidspectral features. It may also be possible to combine the markers fromoxy- and deoxygenated hemoglobin and water with lipid and collagen linesto improve the diagnostics and/or therapeutics of optical imaging and/ortreatment for breast and other types of cancer. Although specificexamples of tissue constituents are discussed, other tissue constituentsand related markers may also be associated with breast cancer and othercancers, and these other constituents are also intended to be covered bythis disclosure.

As an example of the types of spectral signatures that may exist, invivo investigations of progressive changes in rat mammary gland tumorswere conducted using near-infrared spectroscopy with a Fourier-transforminfrared spectrometer. In one embodiment, FIG. 74 shows the typicalspectra of the cancerous site of the treated rat and the correspondingsite of the normal rat. FIG. 74A shows the logarithm of the inverse ofreflection spectra 7400, while FIG. 74B shows their second derivativespectra 7450. The curves 7401, 7451 correspond to the spectra of thecancerous sites, while 7402, 7452 correspond to the spectra of thenormal sites. Since the second derivative techniques may be useful inthe analyses of NIR spectra to minimize baseline offsets and to resolveoverlapping absorption without compromising signal-to-noise, FIG. 74Bmay be used for interpretation of the spectral changes.

In FIG. 74B identification may be made of several of the spectralfeatures. In particular, there are DNA bands near 1471 nm and 1911 nm,while there are water bands near 967 nm, 1154 nm, 1402 nm, and 1888 nm.Moreover, there are lipid bands near 1209 nm, 1721 nm and 1764 nm, andthere are protein bands near 2055 nm, 2172 nm and 2347 nm. The NIRspectra of FIG. 74 show that the DNA and water contents in the canceroustissue may be higher than those in normal tissues. On the other hand,the lipid content in the cancerous tissue may be less than the lipidcontent in normal tissues. With protein contents, however, littledifference may be found between the normal and cancerous tissue.

These experiments on rats with breast cancer were also used to observethe temporal progression of the cancer. In this embodiment, as thecancer grew, the lipid band intensity decreased, and this band alsoshifted to higher wavelengths, and collagen peaks appeared in thetissues. In FIG. 75, the second derivative spectral changes 7500 wereinvestigated in the 1600 nm to 1800 nm wavelength range over severalweeks. An early cancer was detected in the 5th week, and then it grewrapidly from the 6th 7501 to the 7th 7502 week. The cancer's temporalprogression through the 8th 7503, 9th 7504, 10th 7505 and 11th 7506 weekare shown in the various curves in FIG. 75. With the cancer growth, theintensity of the lipid band in the vicinity of 1721 nm decreased, andthis band shifted to higher wavelengths by 7 nm at the 11th week 7506compared to the wavelength band at the 5th week. The higher wavelengthshift may indicate that an order parameter of the lipids increases withprogressive cancer growth.

Moreover, in the data of FIG. 75 is seen that a new peak appeared as thecancer grew around 1690 nm, which may be assigned to be a collagenabsorption by comparison with the absorptions of standard collagen(c.f., FIG. 78). The higher wavelength shift may be attributable to theformation of elastic fibers in the lipid layer with collagen induced inthe cancer tissues, thus leading to an increased order parameter of thelipids. Thus, it can be seen that significant information about breastcancer tissue compared with normal tissue may be obtained byspectroscopy at the longer wavelengths in the near-infrared.

The second derivative spectra may also be insightful for observing andmonitoring changes in tissue as well as characterizing tissue in thenear-infrared wavelength range. As an example, FIG. 76 illustrates thesecond derivative spectra 7600 for cholesterol (similar to oneembodiment of lipids) 7601, collagen 7602, and elastin 7603. The leftcurve 7625 shows the second derivative data over the wavelength range ofabout 1150 nm to 1300 nm, while the right curve 7650 shows the secondderivative data over the wavelength range of about 1600 nm to 1850 nm.These wavelengths show numerous features for cholesterol/lipid 7601,collagen 7602, and elastin 7603, which again emphasizes the added valueof using wavelengths longer than about 1000 nm for cancer diagnostics.

To further illustrate the value of using longer wavelengths in the NIRor SWIR for observing changes in breast cancer and other cancer markers,the spectra of in water, lipids/adipose and collagen of differentvarieties may be studied. As one embodiment, the absorption coefficients7700 are shown in FIG. 77 as a function of wavelength between about 1000nm and 2600 nm. FIG. 77 overlaps the absorption coefficient for water7701, adipose 7702 (forms of adipose include fatty tissue and acids,lipids, and cholesterol), and collagen type I 7703. One may note thatparticular absorption peaks for adipose 7702 and collagen type I 7703align at wavelengths near 1210 nm 7704 and 1720 nm 7705, which alsocorrespond to local minima in water absorption.

Moreover, the NIR spectra for collagen also depend on the type ofcollagen. As an example, FIG. 78 illustrates the absorbance 7800 forfour types of collagen: collagen I 7801, collagen II 7802, collagen III7803, and collagen IV 7804. Collagen I, for instance, may be a majorconstituent of stroma. Also, collagen I and collagen III may be theprincipal collagens of the aorta. Since the spectra of the fourcollagens are distinctive, multicomponent analysis of collagens maypossibly be used to distinguish the type of collagen involved.

The experimental results discussed thus far indicate that breast cancerdetection may benefit from spectroscopy in the NIR and SWIR,particularly wavelengths between approximately 1000-1400 nm and1600-1800 nm. These are wavelength windows that may have deeppenetration into soft tissue, while still falling within lowerabsorption valleys of water. Moreover, the longer wavelengths lead toless scattering in tissue and water, again permitting deeper penetrationof the light. In the NIR and SWIR wavelength range, the spectra ofstandard samples of cholesterol, protein, collagen, elastin and DNA weremeasured to obtain information on their characteristic bands in thespectra of mammary gland tissues. Absorption peaks in the standardsamples occur at the following exemplary wavelengths:

Collagen: 1182 nm, 1360 nm, 1426 nm, 1496 nm, 1569 nm, 1690 nm, 1732 nm;

Lipids: 1157 nm, 1209 nm, 1404 nm, 1721 nm, 1764 nm;

Cholesterol: 918 nm, 1195 nm, 1376 nm, 1585 nm, 1711 nm, 1757 nm;

Protein: 910 nm, 1143 nm, 1186 nm, 1279 nm, 1420 nm, 1503 nm, 1579 nm,1690 nm, 1739 nm, 1799 nm; and

DNA: 1414 nm, 1471 nm, 1626 nm, 1728 nm.

Comparing these absorption features with the data in FIGS. 73-78 showsthat there are absorption features or signatures in the secondderivatives that can be used to monitor changes in, for example,collagen and lipids. By using broadband light and performingspectroscopy in at least some part of the wavelength windows betweenabout 1000-1400 nm and/or 1600-1800 nm, the collagen and lipid changes,or other constituent changes, may be monitored. In one embodiment, forbreast cancer the decrease in lipid content, increase in collagencontent, and possible shift in collagen peaks may be observed byperforming broadband light spectroscopy and comparing normal regions tocancerous regions as well as the absorption strength as a function ofwavelength. The spectroscopy may be in transmission, reflection, diffusereflection, diffuse optical tomography, or some combination. Also, thisspectroscopy may be augmented by fluorescence data, if particular tagsor markers are added. Beyond looking at the absorbance, the dataprocessing may involve also observing the first, second, or higher orderderivatives.

Broadband spectroscopy is one example of the optical data that can becollected to study breast cancer and other types of cancer. However,other types of spectral analysis may also be performed to compare thecollagen and lipid features between different wavelengths and differenttissue regions (e.g., comparing normal regions to cancerous regions),and these methods also fall within the scope of this disclosure. Forexample, in one embodiment just a few discrete wavelengths may bemonitored to see changes in lipid and collagen contents. In a particularembodiment, wavelengths near 1200 nm may be monitored in the secondderivative data of FIG. 76 to measure the cholesterol/lipid peak below1200 nm in 7601 versus the collagen peak above 1200 nm in 7602. In yetanother embodiment, the absorption features in FIG. 73 may be reliedupon to monitor the lipid content 7305 by measuring near 1200 nm and thecollagen content 7306 by measuring near 1300 nm. Although theseembodiments use only two wavelengths, any number of wavelengths may beused and are intended to be covered by this disclosure.

Thus, a breast cancer monitoring system, or a system to monitordifferent types of cancers, may comprise broadband light sources anddetectors to permit spectroscopy in transmission, reflection, diffuseoptical tomography, or some combination. In one particular embodiment,high signal-to-noise ratio may be achieved using a fiber-basedsuper-continuum light source (described further herein). Other lightsources may also be used, including a plurality of laser diodes,super-luminescent laser diodes, or fiber lasers.

Wavelength ranges that may be advantageous for cancer detection includethe NIR and SWIR windows (or some part of these windows) between about1000-1400 nm and 1600-1800 nm. These longer wavelengths fall withinlocal minima of water absorption, and the scattering loss decreases withincreasing wavelength. Thus, these wavelength windows may permitrelatively high penetration depths. Moreover, these wavelength rangescontain information on the overtone and combination bands for variouschemical bonds of interest, such as hydrocarbons.

These longer wavelength ranges may also permit monitoring levels andchanges in levels of important cancer tissue constituents, such aslipids and collagen. Breast cancer tissue may be characterized bydecreases in lipid content and increases in collagen content, possiblywith a shift in the collagen peak wavelengths. The changes in collagenand lipids may also be augmented by monitoring the levels of oxy- anddeoxy-hemoglobin and water, which are more traditionally monitoredbetween 600-1000 nm. Other optical techniques may also be used, such asfluorescent microscopy.

To permit higher signal-to-noise levels and higher penetration depths,higher intensity or brightness of light sources may be used. With thehigher intensities and brightness, there may be a higher risk of pain orskin damage. At least some of these risks may be mitigated by usingsurface cooling and focused infrared light, as further described herein.

Laser Experiments: Penetration Depth, Focusing, Skin Cooling

Some preliminary experiments show the feasibility of using focusedinfrared light for non-invasive procedures, or other procedures whererelatively shallow vessels below the skin are to be thermally coagulatedor occluded with minimum damage to the skin upper layers. In oneembodiment, the penetration depth and optically induced thermal damagehas been studied in chicken breast samples. Chicken breast may be areasonable optical model for smooth muscle tissue, comprising water,collagen and proteins. Commercially available chicken breast sampleswere kept in a warm bath (˜32 degree Celsius) for about an hour, andthen about half an hour at room temperature in preparation for themeasurements.

An exemplary set-up 7900 for testing chicken breast samples usingcollimated light is illustrated in FIG. 79. The laser light 7901 near980 nm, 1210 nm, or 1700 nm may be provided from one or more laserdiodes or fiber lasers, as described further below. In this instance,laser diodes were used, which comprise a plurality of laser diodeemitters that are combined using one or more multiplexers (particularlyspatial multiplexers), and then the combined beam is coupled into amulti-mode fiber (typically 100 microns to 400 microns in diameter). Theoutput from the laser diode fiber was then collimated using one or morelenses 7902. The resulting beam 7903 was approximately round with a beamdiameter of about 3 mm. The beam diameter was verified by blademeasurements (i.e., translating a blade across the beam). Also, thetime-averaged power was measured in the nearly collimated section afterthe lens using a large power meter. The chicken breast samples 7906 weremounted in a sample holder 7905, and the sampler holder 7905 was mountedin turn on a translation stage 7904 with a linear motor that could moveperpendicular to the incoming laser beam. Although particular details ofthe experiment are described, other elements may be added or eliminated,and these alternate embodiments are also intended to be covered by thisdisclosure.

For these particular experiments, the measured depth of damage (inmillimeters) versus the incident laser power (in Watts) is shown 8000 inFIG. 80. In this embodiment, laser diodes were used at wavelengths near980 nm, 1210 nm and 1700 nm. The curve 8001 corresponds to about 980 nm,the curve 8002 corresponds to about 1210 nm, and the curve 8003corresponds to about 1700 nm. It may be noted that there is a thresholdpower, above which the damage depth increases relatively rapidly. Forexample, the threshold power for wavelengths around 980 nm may be about8 W, the threshold power for wavelengths around 1210 nm may be 3 W, andthe threshold power for wavelengths around 1700 nm may be about 1 W. Thethreshold powers may be different at the different wavelengths becauseof the difference in water absorption (e.g., 7701 in FIG. 77). Part ofthe difference in threshold powers may also arise from the absorption ofproteins such as collagen (e.g., 7703 in FIG. 77). After a certain powerlevel, the damage depth appears to saturate: i.e., the slope flattensout as a function of increasing pump power.

In one embodiment, if the penetration depth is defined as the depthwhere damage begins to approximately saturate, then for wavelengths ofabout 980 nm 8001 the penetration depth 8006 may be defined asapproximately 4 mm, for wavelengths of about 1210 nm 8002 thepenetration depth 8005 may be defined as approximately 3 mm, and forwavelengths of about 1700 nm 8003 the penetration depth 8004 may bedefined as approximately 2 mm. These are only approximate values, andother values and criteria may be used to define the penetration depth.It may also be noted that the level of damage at the highest powerpoints differs at the different wavelengths. For example, at the highestpower point of 8003 near 1700 nm, much more damage is observed, showingevidence of even boiling and cavitation. This may be due to the higherabsorption level near 1700 nm (e.g., 7701 in FIG. 77). On the otherhand, at the highest power point 8001 near 980 nm, the damage is not ascatastrophic, but the spot size appears larger. The larger spot size maybe due to the increased scattering at the shorter wavelengths (e.g.,7701 in FIG. 77). Based on data 8000 such as in FIG. 80, it may bepossible to select the particular wavelength for the laser beam to beused in the non-invasive procedure.

Even near wavelengths such as described in FIG. 80, the particularwavelength selected may be more specifically defined based on the targettissue of interest. In one particular embodiment, the vessel lumen maybe modeled as water, and for this example assume that wavelengths in thevicinity of 980 nm are being selected to create thermal coagulation orocclusion. FIG. 81 shows the optical absorption or density as a functionof wavelength 8100 between approximately 700 nm and 1300 nm. Curves areshown for the water absorption 8101, hemoglobin Hb absorption 8102, andoxygenated hemoglobin HbO2 8103. In this example, two particularwavelengths are compared: 980 nm 8104 and 1075 nm 8105. For instance,980 nm may be generated using one or more laser diodes, while 1075 nmmay be generated using an ytterbium-doped fiber laser. If maximizing thepenetration depth is the significant problem, then 1075 nm 8105 may bepreferred, since it falls near a local minimum in water 8101, hemoglobin8102, and oxygenated hemoglobin 8103 absorption. On the other hand, ifthe penetration depth at 980 nm 8104 is adequate and the problem is togenerate heat through water absorption, then 980 nm 8104 may be apreferred wavelength for the light source because of the higher waterabsorption. This wavelength range is only meant to be exemplary, butother wavelength ranges and particular criteria for selecting thewavelength may be used and are intended to be covered by thisdisclosure.

In another embodiment, focused infrared light has been used to preservethe top layer of a tissue while damaging nerves at a deeper level. Forinstance, FIG. 82 illustrates the set-up 8200 used for the focusedinfrared experiments. In this embodiment, a lens 8201 is used to focusthe light. Although a single lens is shown, either multiple lenses, GRIN(gradient index) lenses, curved mirrors, or a combination of lenses andmirrors may be used. In this particular example, the tissue 8204 isplaced between two microscope slides 8202 and 8203 for in vitroexperiments. The tissue 8204 is renal artery wall either from porcine orbovine animals (about 1.2 mm thick sample)—i.e., this is the arteryleading to the kidneys, and it is the artery where typically renaldenervation may be performed to treat hypertension. For this example,the minimum beam waist 8205 falls behind the tissue, and the intensitycontrast from the front of the tissue (closest to the lens) to the backof the tissue (furthest from the lens) is about 4:1. These areparticular ranges used for this experiment, but other values andlocations of minimum beam waist may also be used and intended to becovered by this disclosure.

For a particular embodiment, histology of the renal artery is shown inFIG. 83A for no laser exposure 8300 and shown in FIG. 83B with focusedinfrared laser exposure 8350. In this experiment, the beam diameterincident on the lens was about 4 mm, and the distance from the edge ofthe flat side of lens to the minimum beam waist was about 3.75 mm. Thebeam diameter on the front side of the renal artery (i.e., theendothelium side) was about 1.6 mm, and the beam diameter on the backside of the renal artery was about 0.8 mm. In FIG. 83A with no laserexposure, the layers of the artery wall may be identified: top layer ofendothelium 8301 that is about 0.05 mm thick, the media comprisingsmooth muscle cells or tissue 8302 that is about 0.75 mm thick, and theadventitia 8303 comprising some of the renal nerves 8304 that is about1.1 mm thick. These are particular values for this experiment, and otherlayers and thicknesses may also be used and are intended to be coveredby this disclosure.

The histology with focused infrared light exposure 8350 is illustratedin FIG. 83B. The laser light used is near 1708 nm from a cascaded Ramanoscillator (described in greater detail herein), and the power incidenton the tissue is about 0.8 W and the beam is scanned across the tissueat a rate of approximately 0.4 mm/sec. The various layers are stillobservable: the endothelium 8351, the media 8352, and the adventitia8353. With this type of histology, the non-damaged regions remain darker(similar to FIG. 83A), while the laser induced damaged regions turnlighter in color. In this example, the endothelium 8351 and top layer ofthe media 8352 remain undamaged—i.e., the top approximately 0.5 mm isthe undamaged region 8356. The laser damaged region 8357 extends forabout 1 mm, and it includes the bottom layer of the media 8352 and muchof the adventitia 8353. The renal nerves 8354 that fall within thedamage region 8357 are also damaged (i.e., lighter colored). On theother hand, the renal nerves beyond this depth, such as 8355, may remainundamaged.

Thus, by using focused infrared light near 1708 nm in this example, thetop approximately 0.5 mm of the renal artery is spared from laserdamage. It should be noted that when the same experiment is conductedwith a collimated laser beam, the entire approximately 1.5 mm is damaged(i.e., including regions 8356 and 8357). Therefore, the cone of lightwith the lower intensity at the top and the higher intensity toward thebottom may, in fact, help preserve the top layer from damage. Thereshould be a Beer's Law attenuation of the light intensity as the lightpropagates into the tissue. For example, the light intensity shouldreduce exponentially at a rate determined by the absorption coefficient.In these experiments it appears that the focused light is able toovercome the Beer's law attenuation and still provide contrast inintensity between the front and back surfaces.

In another embodiment, experiments have also been conducted ondermatology samples with surface cooling, and surface cooling is shownto preserve the top layer of the skin during laser exposure. In thisparticular example, the experimental set-up 8400 is illustrated in FIG.84. The skin sample 8404, or more generally sample under test, is placedin a sample holder 8403. The sample holder 8403 has a cooling side 8401and a heating side 8402. The heating side 8402 comprises a heater 8405,which may be adjusted to operate around 37 degrees Celsius—i.e., closeto body temperature. The cooling side 8401 is coupled to an ice-waterbath 8407 (around 2 degrees Celsius) and a warm-water bath 8406 (around37 degrees Celsius) through a switching valve 8408. The entire sampleholder 8403 is mounted on a linear motor 8409, so the sample can bemoved perpendicular 8410 to the incoming light beam.

In this embodiment, the light is incident on the sample 8404 through asapphire window 8411. The sapphire material 8411 is selected because itis transparent to the infrared wavelengths, while also being a goodthermal conductor. Thus, the top layer of the sample 8404 may be cooledby being approximately in contact with the sapphire window 8411. Thelaser light 8412 used is near 1708 nm from a cascaded Raman oscillator(described in greater detail herein), and one or more collimating lenses8413 are used to create a beam with a diameter 8414 of approximately 2mm. This is one particular embodiment of the sample surface coolingarrangement, but other apparatuses and methods may be used and areintended to be covered by this disclosure.

Experimental results obtained using the set-up of FIG. 84 are includedin FIG. 18. In this example, FIG. 85 shows the MTT histochemistry ofhuman skin 8500 treated with ˜1708 nm laser (5 seconds pre-cool; 2 mmdiameter spot exposure for 3 seconds) at 725 mW (A 8501, B 8502)corresponding to about 70 J/cm2 average fluence, and 830 mW (C 8503, D8504) corresponding to about 80 J/cm2 average fluence. The images inFIG. 85 show that the application of a cold window was effective inprotecting the epidermis 8505 (darker top layer) and the topapproximately 0.4 or 0.5 mm of the dermis 8506. As before, the darkerregions of the histology correspond to undamaged regions, while thelighter regions correspond to damaged regions. In contrast, when nosurface cooling is applied, then thermal damage to the dermis occurs inthe epidermis and dermis where the laser exposure occurs, and thethermal damage extends to about 1.3 or 1.4 mm or more from the skinsurface. Thus, surface cooling applied to the skin may help to reduce oreliminate damage to the top layer of the skin under laser exposure.

In summary, experiments verify that infrared light, such as near 980 nm,1210 nm, or 1700 nm, may achieve penetration depths betweenapproximately 2 mm to 4 mm or more. The top layer of skin or tissue maybe spared damage under laser exposure by focusing the light beyond thetop layer, applying surface cooling, or some combination of the two.These are particular experimental results, but other wavelengths,methods and apparatuses may be used for achieving the penetration andminimizing damage to the top layer and are intended to be covered bythis disclosure. In an alternate embodiment, it may be beneficial to usewavelengths near 1310 nm if the absorption from skin constituents (FIG.77), such as collagen 7703, adipose 7702 and elastin 7704, are to beminimized. The water absorption 7701 near 1310 nm may still permit apenetration depth of approximately 1 cm, or perhaps less. In yet anotherembodiment, wavelengths near 1210 nm may be beneficial, if penetrationdepths on the order of 3 mm are adequate and less scattering loss (e.g.7701 in FIG. 77) is desired. Any of FIG. 68, 73, 75, 77, or 78 may beused to select these or other wavelengths to achieve the desiredpenetration depth and to also perhaps target particular tissue ofinterest, and these alternate embodiments are also intended to becovered by this disclosure.

Laser Systems for Therapeutics or Diagnostics

Infrared light sources can be used for diagnostics and therapeutics in anumber of medical applications. For example, broadband light sources canadvantageously be used for diagnostics, while narrower band lightsources can advantageously be used for therapeutics. In one embodiment,selective absorption or damage can be achieved by choosing the laserwavelength to lie approximately at an absorption peak of particulartissue types. Also, by using infrared wavelengths that minimize waterabsorption peaks and longer wavelengths that have lower tissuescattering, larger penetration depths into the biological tissue can beobtained. In this disclosure, infrared wavelengths include wavelengthsin the range of approximately 0.9 microns to 10 microns, withwavelengths between about 0.98 microns and 2.5 microns more suitable forcertain applications.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. In this disclosure, the term “damage” refers to affecting atissue or sample so as to render the tissue or sample inoperable. Forinstance, if a particular tissue normally emits certain signalingchemicals, then by “damaging” the tissue is meant that the tissuereduces or no longer emits that certain signaling chemical. The term“damage” and or “damaged” may include ablation, melting, charring,killing, or simply incapacitating the chemical emissions from theparticular tissue or sample. In one embodiment, histology orhistochemical analysis may be used to determine whether a tissue orsample has been damaged.

As used throughout this disclosure, the term “spectroscopy” means that atissue or sample is inspected by comparing different features, such aswavelength (or frequency), spatial location, transmission, absorption,reflectivity, scattering, refractive index, or opacity. In oneembodiment, “spectroscopy” may mean that the wavelength of the lightsource is varied, and the transmission, absorption or reflectivity ofthe tissue or sample is measured as a function of wavelength. In anotherembodiment, “spectroscopy” may mean that the wavelength dependence ofthe transmission, absorption or reflectivity is compared betweendifferent spatial locations on a tissue or sample. As an illustration,the “spectroscopy” may be performed by varying the wavelength of thelight source, or by using a broadband light source and analyzing thesignal using a spectrometer, wavemeter, or optical spectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium. In anotherembodiment, the infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam may be coupled to a gain mediumto excite the gain medium, which in turn may amplify another inputoptical signal or beam. In one particular example, the gain medium maybe a doped fiber, such as a fiber doped with ytterbium, erbium, and/orthulium. In another embodiment, the gain medium may be a fused silicafiber or a fiber with a Raman effect from the glass. In one embodiment,the “pump laser” may be a fiber laser, a solid state laser, a laserinvolving a nonlinear crystal, an optical parametric oscillator, asemiconductor laser, or a plurality of semiconductor lasers that may bemultiplexed together. In another embodiment, the “pump laser” may becoupled to the gain medium by using a fiber coupler, a dichroic mirror,a multiplexer, a wavelength division multiplexer, a grating, or a fusedfiber coupler.

As used throughout this document, the term “super-continuum” and/or“supercontinuum” and/or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth of at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, the Ramaneffect, modulational instability, and self-phase modulation.

As used throughout this disclosure, the terms “optical light” and/or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and/or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and/or “optical beam” and/or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

As used throughout this document, the terms “near” or “about” or thesymbol “˜” refer to one or more wavelengths of light with wavelengthsaround the stated wavelength to accomplish the function described. Forexample, “near 1720 nm” may include wavelengths of between about 1680 nmand 1760 nm. In one embodiment, the term “near 1720 nm” refers to one ormore wavelengths of light with a wavelength value anywhere betweenapproximately 1700 nm and 1740 nm. Similarly, as used throughout thisdocument, the term “near 1210 nm” refers to one or wavelengths of lightwith a wavelength value anywhere between approximately 1170 nm and 1250nm. In one embodiment, the term “near 1210 nm” refers to one or morewavelengths of light with a wavelength value anywhere betweenapproximately 1190 nm and 1230 nm.

While exemplary embodiments are described above, it is not intended thatthese embodiments describe all possible forms of the disclosure. Rather,the words used in the specification are words of description rather thanlimitation, and it is understood that various changes may be madewithout departing from the spirit and scope of the disclosure.Additionally, the features of various implementing embodiments may becombined to form further embodiments of the disclosure. While variousembodiments may have been described as providing advantages or beingpreferred over other embodiments with respect to one or more desiredcharacteristics, as one skilled in the art is aware, one or morecharacteristics may be compromised to achieve desired system attributes,which depend on the specific application and implementation. Theseattributes include, but are not limited to: cost, strength, durability,life cycle cost, marketability, appearance, packaging, size,serviceability, weight, manufacturability, ease of assembly, etc. Theembodiments described herein that are described as less desirable thanother embodiments or prior art implementations with respect to one ormore characteristics are not outside the scope of the disclosure and maybe desirable for particular applications.

What is claimed is:
 1. A measurement system comprising: an array of laser diodes to operate in a pulsed mode and to generate light having one or more optical wavelengths that includes at least one near-infrared wavelength, the array of laser diodes comprising one or more Bragg reflectors, wherein at least a portion of the light generated by the array is configured to penetrate tissue comprising skin; a detection system comprising an infrared camera and a first receiver comprising a plurality of detectors, wherein the plurality of detectors comprises one or more detector arrays, and wherein the detection system is synchronized to the pulsing of the array of laser diodes, and wherein the detection system further comprises one or more filters in front of at least a part of the detection system to select some of the one or more optical wavelengths; the first receiver configured to receive at least a first portion of light reflected from the tissue from at least a part of the array of laser diodes, and wherein at least one of the plurality of detectors is coupled to one or more analog-to-digital converters and a processor; the infrared camera configured to receive at least a second portion of light reflected from the tissue from the at least a part of the array of laser diodes, wherein the infrared camera is configured to generate data based at least in part on the portion of the light received, and the infrared camera is further coupled to the processor; a first lens system coupled to the plurality of detectors, and one or more lenses coupled to the infrared camera; wherein the measurement system is configured to generate an image using at least part of the data from the detection system; the detection system configured to non-invasively measure blood in blood vessels within or below a dermis layer within the skin based at least in part on near-infrared diffuse reflection from the skin; the detection system configured to measure absorption of hemoglobin in the near-infrared wavelength between 700 nanometers and 1300 nanometers; and wherein the processor is configured to compare the absorption of hemoglobin between different spatial locations of tissue; and wherein the first receiver is configured to perform a time-of-flight measurement by measuring a time difference between the generated light from the array of laser diodes and the at least a first portion of light reflected from the tissue from at least a part of the array of laser diodes, and wherein the measurement system is configured to receive and process at least a portion of the time-of-flight measurement.
 2. The measurement system of claim 1, wherein the measurement system is configured to measure one or more physiological parameters based at least in part on the non-invasively measured blood within the tissue, and wherein the one or more physiological parameters are generated at least in part by using a Fourier transform of at least some of the at least part of the data from the detection system.
 3. The measurement system of claim 1, wherein the array of laser diodes is configured to increase signal-to-noise ratio of a processor output by increasing a light intensity from at least one of the laser diodes of the array of laser diodes, and wherein the array of laser diodes is configured to further increase signal-to-noise ratio of the processor output by increasing a pulse rate of the at least one of the laser diodes of the array of laser diodes.
 4. The measurement system of claim 1, wherein the infrared camera is further configured to: capture light while the array of laser diodes is off and convert the captured light into a first signal, capture light while at least one of the laser diodes of the array of laser diodes is on and convert the captured light into a second signal, the captured light including at least some light from the second portion of light reflected from the tissue from the at least a part of the array of laser diodes, and the measurement system further configured to improve a signal-to-noise ratio of the image by differencing the first signal and the second signal.
 5. The measurement system of claim 1, wherein the array of laser diodes comprises a first array of laser diodes operating at a first near-infrared wavelength and a second array of laser diodes operating at a second near-infrared wavelength, and wherein a processor output is generated at least in part by comparing the reflected light at the first near-infrared wavelength with the reflected light at the second near-infrared wavelength.
 6. The measurement system of claim 1, further comprising one or more polarizers arranged in front of at least a portion of the detection system.
 7. The measurement system of claim 1, wherein the processor is configured to differentiate between a region in the skin having a vein and a region in the skin without distinct veins; and wherein the measurement system is configured to apply regression signal processing methodologies or multivariate data analysis or component analysis techniques.
 8. A measurement system comprising: an array of laser diodes to operate in a pulsed mode and to generate light having one or more optical wavelengths that includes at least one near-infrared wavelength, the array of laser diodes comprising one or more Bragg reflectors, wherein the light from at least some of the laser diodes in the array of laser diodes is spatially combined, and wherein at least a portion of the light generated by the array is configured to penetrate tissue comprising skin; a detection system comprising an infrared camera, wherein the detection system is synchronized to the pulsing of the array of laser diodes, and wherein the detection system further comprises one or more filters in front of at least a part of the detection system to select some of the one or more optical wavelengths; the infrared camera configured to receive at least a first portion of light reflected from the tissue from at least a part of the array of laser diodes, wherein a first lens system is coupled to the infrared camera, wherein the infrared camera is configured to generate data based at least in part on the portion of the light received, and the infrared camera is further coupled to a processor; wherein the measurement system is configured to generate an image using at least part of the data from the detection system; the detection system configured to non-invasively measure blood in blood vessels within or below a dermis layer within the skin based at least in part on near-infrared diffuse reflection from the skin; the detection system configured to measure absorption of hemoglobin in the near-infrared wavelength between 700 nanometers and 1300 nanometers; wherein the processor is configured to compare the absorption of hemoglobin between different spatial locations of tissue; wherein the measurement system is configured to measure one or more physiological parameters based at least in part on the non-invasively measured blood within the tissue, wherein the one or more physiological parameters are generated at least in part by using a Fourier transform of at least some of the at least part of the data from the detection system.
 9. The measurement system of claim 8, wherein the detection system further comprises a first receiver comprising a plurality of detectors, wherein the plurality of detectors comprises one or more detector arrays, and wherein the first receiver is configured to receive at least a second portion of light reflected from the tissue from the at least a part of the array of laser diodes, and wherein at least one of the plurality of detectors is coupled to one or more analog-to-digital converters and the processor; and wherein the first receiver is configured to perform a time-of-flight measurement by measuring a time difference between the generated light from the array of laser diodes and the at least a second portion of light reflected from the tissue from the at least a part of the array of laser diodes, and wherein the measurement system is configured to receive and process at least a portion of the time-of-flight measurement.
 10. The measurement system of claim 8, wherein the array of laser diodes comprises a first array of laser diodes operating at a first near-infrared wavelength and a second array of laser diodes operating at a second near-infrared wavelength, and wherein the one or more physiological parameters are generated at least in part by comparing the reflected light at the first near-infrared wavelength with the reflected light at the second near-infrared wavelength.
 11. The measurement system of claim 8, wherein the array of laser diodes is configured to increase signal-to-noise ratio of a processor output by increasing a light intensity from at least one of the laser diodes of the array of laser diodes, and wherein the array of laser diodes is configured to further increase signal-to-noise ratio of the processor output by increasing a pulse rate of the at least one of the laser diodes of the array of laser diodes.
 12. The measurement system of claim 8, wherein the infrared camera is further configured to: capture light while the array of laser diodes is off and convert the captured light into a first signal, capture light while at least one of laser diode of the array of laser diodes is on and convert the captured light into a second signal, the captured light including at least some light from the first portion of light reflected from the tissue from the at least a part of the array of laser diodes, and the measurement system further configured to improve a signal-to-noise ratio of the image by differencing the first signal and the second signal.
 13. The measurement system of claim 8, further comprising one or more polarizers in front of at least a portion of the detection system.
 14. The measurement system of claim 8, wherein the processor is configured to differentiate between a region in the skin having a vein and a region in the skin without distinct veins; and wherein the measurement system is configured to apply regression signal processing methodologies or multivariate data analysis or component analysis techniques.
 15. A remote sensing system, comprising: an array of laser diodes configured to generate light having an initial light intensity and one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers, wherein at least a portion of the array of laser diodes comprises one or more Bragg reflectors, wherein the at least a portion of the array of laser diodes is configured to be modulated, and wherein the light from at least some of the laser diodes in the array of laser diodes is spatially combined; a beam splitter configured to receive a portion of the light from the array of laser diodes and to direct at least some of the portion of the light from the array of laser diodes to an object, wherein the beam splitter is configured to separate the received portion of the light into a plurality of spatially separated lights; a detection system comprising a photodiode array coupled to one or more lenses and one or more spectral filters, wherein the photodiode array is further coupled to one or more analog-to-digital converters and a processor; wherein the detection system is configured to receive at least a portion of light reflected from the object, wherein the detection system is configured to be synchronized to the at least a portion of the array of laser diodes comprising Bragg reflectors; wherein the detection system is further configured to perform a time-of-flight measurement, wherein the time-of-flight measurement comprises measuring a time difference between the generated light from the at least a portion of the array of laser diodes and the at least a portion of light reflected from the object; a camera system coupled to a lens system and the processor, the camera system further configured to capture one or more images including at least a part of the object; wherein the remote sensing system is configured to generate a two-dimensional or three-dimensional mapping using at least a portion of the one or more images and at least a portion of the time-of-flight measurement; wherein the remote sensing system is configured to improve signal-to-noise ratio of at least a portion of the two-dimensional or three-dimensional mapping by increasing light intensity of the array of laser diodes relative to the initial light intensity; and wherein the remote sensing system is coupled to a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, one or more buttons or knobs, a microprocessor and a touch screen.
 16. The remote sensing system of claim 15, wherein at least some of the laser diodes in the array of laser diodes operate at a wavelength near 940 nanometers.
 17. The remote sensing system of claim 16, wherein the at least a portion of the array of laser diodes is configured to be modulated comprises a pulse duration of approximately 0.5 to 2 nanoseconds.
 18. The remote sensing system of claim 17, wherein the remote sensing system further comprises one or more polarizers in front of at least a portion of the detection system or the camera system.
 19. The remote sensing system of claim 17, wherein the detection system or the camera system is further configured to: generate a first signal responsive to light received while the array of laser diodes is off; and generate a second signal responsive to light received while at least part of the array of laser diodes is on, the light received while at least part of the array of laser diodes is on including at least some light reflected from the object; and wherein the remote sensing system is configured to compare the first signal and the second signal and to generate the two-dimensional or three-dimensional mapping at least in part based on the comparison.
 20. The remote sensing system of claim 15, wherein the at least a portion of the array of laser diodes is configured to be modulated has a phase, and wherein the detection system is configured to lock onto the phase; wherein the at least a portion of the array of laser diodes is configured to be modulated comprises a pulse repetition rate between one (1) kilohertz and about 100 megahertz; and wherein the remote sensing system is configured to use a lock-in technique to further improve the signal-to-noise ratio of at least a portion of the two-dimensional or three-dimensional mapping. 